N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of nr2b

ABSTRACT

The present disclosure relates to N-alkylaryl-5-oxyaryl-octadihydrocyclopent[c]pyrrole negative allosteric modulators of NR2B receptors useful in the treatment of neurological diseases having the Formula I: 
     
       
         
         
             
             
         
       
     
     where R 1 , R 2 , L 1 , L 2 , X, Y, and Y′ are described therein.

This application is a continuation of U.S. application Ser. No.16/991,684, filed Aug. 12, 2020, which is a continuation of U.S.Application Ser. No. 16/255,500, filed Jan. 23, 2019, which is acontinuation of U.S. application Ser. No. 15/506,592, filed Feb. 24,2017, which is the national phase application of PCT Application No.PCT/US2015/051694, filed Sep. 23, 2015, which claims priority to U.S.Provisional Patent Application Ser. No. 62/056,284, filed Sep. 26, 2014,the entireties of all of which are incorporated herein by reference.

FIELD

The present disclosure relates to compounds that selectively modulatethe activity of NR1/NR2B receptors.

BACKGROUND

The NMDA receptor is arguably an important signaling mechanism in thehuman brain. The brain processes a complex array of information to allowhumans to function, storing information from the past and analyzing thisinformation in the context of the present to respond and plan for thefuture. These incredibly complex computations are mediated at themolecular level by the continual adjustment of the strength of synapses,the nodes for communication between nerve cells (estimated at about 60trillion in the human brain).

Glutamate is the major excitatory neurotransmitter in the brain,utilized at 80% of these synapses. NMDA receptors are one of threeclasses that mediate synaptic transmission using glutamate. NMDAreceptors play a critical role in regulating the strength of synapses,that is, in regulating synaptic plasticity. Thus, the NMDA receptor isat the molecular core of brain function, and in particular the cognitivefunctions of learning and memory. These facts underlie the tremendoustherapeutic utility of modulating NMDA receptor function with new drugsto treat a broad range of neuropsychiatric disease and cognitivedysfunction.

The molecular basis of NMDA receptor function is increasingly wellunderstood. The NMDA receptor is composed of four protein subunits, twoNR1 subunits and two NR2 subunits. An NR1 subunit derived from a singlegene is ubiquitously expressed throughout the brain and is common to allNMDA receptors. However, the four different NR2 subunits. NR2A-D, arederived from separate genes that are differentially expressed indifferent brain regions and by distinct populations of neurons within aparticular region. Furthermore, individual neurons may express more thanone NR2 subunit and individual NMDA receptors expressed by such neuronsmay contain two of the same NR2 subunits (for example, 2 NR2B subunits)or two different subunits (one NR2A and one NR2B subunit). Therefore, adrug that selectively modulates the activity of one NR2 subunit may doso at receptors that express two of the targeted subunits, or only oneof the targeted subunits. Thus there is a need for new treatments fordiseases related to the NR1/NR2B receptor.

SUMMARY

In an aspect, compounds of formula I are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein:L₁ is straight or branched C₁-C₅ alkyl optionally substituted with oneor more substituents selected from the group consisting of OH, OR₁₀,NH₂, NHR₁₀, and N(R₁₀)(R₁₀′) provided that no more than one oxygen ornitrogen is attached to any carbon; orL₁ is selected from the group consisting of —C(O)—,—C(O)—C₁-C₃alkylenyl-, —C(O)O—C₁-C₃alkylenyl-, —S(O)₂—, —S(O)₂NH—,—C(O)NH—, —C(O)NR₁₀—, and a bond;

-   -   Each R₁₀ and R₁₀′ is independently selected from the group        consisting of H; C₁-C₆ alkyl optionally substituted with one or        more substituents selected from the group consisting of OH,        O—C₁-C₅ alkyl, OPO₃ ⁻²M₂, OP(O)(OH)₂, OC(O)alkyl, and        OC(O)O-alkyl where M is a monovalent metal cation; and        cycloalkyl optionally substituted with one or more substituents        selected from the group consisting of OH and O—C₁-C₅ alkyl        provided that no more than one oxygen is attached to any carbon;        or R₁₀ and R₁₀′, together with the nitrogen to which they are        attached, may form a heterocycle;        R₁ is cycloalkyl, aryl, or heteroaryl, any of which optionally        substituted with one or more substituents selected from the        group consisting of OH, CN, halogen, —C₁-C₆alkylaryl,        —O—C₁-C₆alkylaryl, O—R₁₀, OPO₃ ⁻²M₂, OP(O)(OH)₂, SH, S—R₁₀,        C₁-C₅ alkyl, branched alkyl, NH₂, NHR₁₀, NHS(O)₂R₁₀,        N(R₁₀)(R₁₀′), and NHCOR₁₀ where M is a monovalent metal cation;        Y and Y′ are independently H, halogen, or C₁-C₅ alkyl;        X is selected from O, S, —S(O)—, and —S(O)₂—;        L₂ is a bond, —(CH₂)_(n)— or —(CHR₁₁)_(n)—;    -   Each R₁₁ is independently selected from the group consisting of        H, —C₁-C₅ alkylenyl-, —CO—C₁-C₅alkylenyl-, and        -alkylenyl-CO-alkylenyl-;        R₂ is phenyl, naphthyl, heteroaryl or bicyclic heteroaryl, each        of which is optionally substituted with one or more substituents        selected from the group consisting of halogen, OH, C₁-C₆alkyl,        OR₁₀, CN, NH₂, NHR₁₀, N(R₁₀)(R₁₀′), -nitro, SH, SR₁₀, SOR₁₀,        SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R₁₀′), CONH₂, CONR₁₀, and        CON(R₁₀)(R₁₀′); and n is 1, 2, or 3.

The present disclosure further pertains to compounds that selectivelymodulate the activity of NMDA receptors that contain an NR2B subunit,which encompasses receptors containing two NR2B subunits or one NR2Bsubunit in combination with one other NR2 subunit (i.e., NR2A/NR2B,NR2B/NR2C, or NR2B/NR2D receptors). Such compounds can decrease theactivity of NR2B-containing NMDA receptors. The present disclosure alsopertains to the therapeutic uses of such compounds. Also described arepharmaceutical formulations, comprising at least one of the disclosedcompounds.

Also described herein are methods of treating a disease susceptible totreatment with a disclosed compound in a patient in need thereof byadministering to the patient an effective amount of a disclosedcompound. Such diseases include, without limitation, neurologicaldysfunction such as Parkinson's disease. Huntington's disease,amyotrophic lateral sclerosis, multiple sclerosis, and seizuredisorders; emotional disorders; depression; bipolar disorder;obsessive-compulsive disorder, and other anxiety disorders.

Compounds or pharmaceutical compositions of the present disclosure maybe used to treat individuals that experience dysfunction caused byabnormal brain development, including but not limited to those sufferingfrom autism and autism spectrum disorders, Fragile X syndrome. RettSyndrome, Angelman syndrome, tuberous sclerosis. Down's syndrome andother forms of mental retardation.

The disclosure further pertains to pharmaceutical compositions thatcomprise an effective amount of a disclosed compound and apharmaceutically acceptable carrier. The compositions are useful fortreating or preventing a disease or disorder. The disclosure includes adisclosed compound provided as a pharmaceutically acceptable prodrug,hydrate, salt, stereoisomer, or mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the X-ray crystallograph of the compound of Example 8.

FIG. 2 is the X-ray crystallograph of the compound of Example 10.

DETAILED DESCRIPTION

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example. “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, CN, —COOH, —CH₂CN,—O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—NHC(O)C₁-C₆alkyl, —C(O)NHC₁-C₆alkyl, —S(O)₂—C₁-C₆alkyl,—S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, N H₂, NH(C₁-C₆alkyl).N(C₁-C₆alkyl)₂, —S(O)₂-C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, andS(O)N(C₁-C₆alkyl)₂. The substituents can themselves be optionallysubstituted. Furthermore when containing two fused rings the aryl groupsherein defined may have an unsaturated or partially saturated ring fusedwith a fully saturated ring. Exemplary ring systems of these aryl groupsinclude indanyl, indenyl, tetrahydronaphthalenyl, andtetrahydrobenzoannulenyl.

Unless otherwise specifically defined. “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 10 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.

“C₁-C₃ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-3 carbon atoms. Examples of a C₁-C3alkyl groupinclude, but are not limited to, methyl, ethyl, propyl and isopropyl.

“C₁-C₃ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-5 carbon atoms. Examples of a C₁-C₅alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

Alkyl is generally lower alkyl, or C₁-C₆ alkyl. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl,isopentyl, neopentyl, and isohexyl.

Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.

“Alkylenyl” as herein defined refers to groups of generalformula—(CH₂)n—where n is an integer from 1 to 6. Suitable examples ofalkylenyl groups include methylenyl, ethylenyl, and propylenyl.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. Examples of alkenyl groups include ethenyl,propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriplebond in the chain. Examples of alkynyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

The term “haloalkyl” refers to straight or branched saturatedhydrocarbon chains containing 1-5 carbon atoms which are substituted atleast one of the carbon with halogen groups such fluorine, chlorine,bromine, iodide. Examples of haloalkyl groups as herein defined includewithout limitation trifluoromethyl, tribromomethyl, and1,1,1-trifluoroethyl.

The term “hydroxyalkyl” refers to straight or branched saturatedhydrocarbon chains containing 1-5 carbon atoms which are substituted atleast one of the carbon with the hydroxyl group.

The term “-alkylaryl” refers to aryl groups connected to an adjacentC1-C6alkyl wherein the linkage is located at the alkyl end. Accordingly,groups such as benzyl, phenylethyl, or mesitylenyl constitute exemplaryrepresentatives of alkylaryl of the present disclosure.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Heterocyclyl” or “heterocycloalkyl” or “heterocycle” monocyclic ringscontaining carbon and heteroatoms taken from oxygen, nitrogen, or sulfurand wherein there is not delocalized a electrons (aromaticity) sharedamong the ring carbon or heteroatoms; heterocyclyl rings include, butare not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl.

“Spirocycle” means bicyclic ring systems with both rings connectedthrough a single atom. The ring can be different in size and nature, oridentical in size and nature. Examples include spiropentane,spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4.4-diaminostilbene-2.2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt.3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “monovalent metal cation” refers to atomic elements that arepositively charged (atoms which have more protons than electrons becausethey have lost electrons). Examples of metal cations include, withoutlimitation, monovalent metal and metalloids of the periodic table. Thesemetal cations include monovalent alkaline metals such Li, K, Na, Rb, orCs, monovalent transition metals such as Cu, Au, or Ag.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomer. Theterm “diastereomer” refers to any member of this set of compounds. Insome examples presented, the synthetic route may produce a singlediateromer or a mixture of diastereomer. In some cases these diateromerswere separated and in other cases a wavy bond is used to indicate thestructural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the disclosure.

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(i.e., using an enzyme).

One aspect of the disclosure relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof, where R₁, R₂, L₁, L₂, X, Y, and Y′are described above.

In one embodiment of the compounds of Formula I, R₁ is aryl orheteroaryl each of which is substituted with one or more substituentsselected from the group consisting of OH, halogen, OR₁₀, SH, SR₁₀, NH₂,NHR₁₀ and NHCOR₁₀.

In another embodiment, wherein R₁ is aryl substituted with onesubstituent selected from the group consisting of OH, OR₁₀, SH, SR₁₀,NH₂, NHR₁₀ and NHCOR₁₀.

In another embodiment of the compounds of Formula I, Y and Y′ arehydrogen.

In another embodiment of the compounds of Formula I, Y and Y′ arehalogen. In other embodiments of the compounds of Formula I, Y and Y′are fluorine.

In another embodiment of the compounds L₂ is a bond.

In another embodiment of the compounds of Formula I, n is 1.

In another embodiment of the compounds of Formula I, n is 2.

In yet another embodiment of the compounds of Formula I, R₂ is phenyloptionally substituted with one or more halogen, OH, OR₁₀, CN, NH₂,NHR₁₀, N(R₁₀)(R₁₀′), SH, SR₁₀, SOR₁₀, SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R₁₀′),CONH₂, CONR₁₀, CON(R₁₀)(R₁₀′).

In another embodiment, R₂ is phenyl substituted with one or morehalogen.

In another embodiment of the compounds of Formula I, L₁ is branchedC₁-C₅ alkyl substituted with one or more substituents selected from thegroup consisting of OH, OR₁₀, NH₂, NHR₁₀, and N(R₁₀)(R₁₀′) provided thatno more than one oxygen or nitrogen is attached to any carbon of L₁.

In another embodiment of the compounds of Formula I, L₁ is straightC₁-C₅ alkyl substituted with one or more substituents selected from thegroup consisting of OH, OR₁₀, NH₂, NHR₁₀, and N(R₁₀)(R₁₀′) provided thatno more than one oxygen or nitrogen is attached to any carbon of L₁.

Other embodiments of the disclosure relate to compounds of Formula Iwhere L₁ is straight or branched C₁-C₅ alkyl substituted with OH.

In some embodiments of the compounds of Formula I, L₁ is—C(O)—C₁-C₃alkylenyl-.

In other embodiments of the compounds of Formula I, L₂ is unsubstitutedstraight or branched C₁-C₅ alkyl.

In some embodiments of the compounds of Formula I, L₂ is —CH₂—.

Yet in other embodiments, the disclosure describes compounds of FormulaI where X is O.

In some embodiments of the compounds of Formula I, X is S.

In other embodiments, the disclosure relates to compounds of Formula Iwhere R₁ is aryl or heteroaryl, both of which are optionally substitutedwith one or more substituents selected from the group consisting of OHand halogen.

In other embodiments of the compounds of Formula I, R₁ is phenylsubstituted with OH and halogen.

In yet another embodiment of the compounds of Formula I, R₁ is abicyclic heteroaryl substituted with OH and halogen.

In some embodiments, the present disclosure rather includes compounds ofFormula I where any hydrogen atom may be replaced with a deuterium atom.

In other embodiments, tautomers of the compounds of Formula I are alsodescribed.

Other embodiments of Formula I relate to compounds of Formula (Ia):

wherein:A, B, C, D, and E are independently N or CR_(x);------- is an optional double bond;

X is CH or C; U is OH or O;

Y and Y′ are independently H, halogen, or C₁-C₆ alkyl;

R₃ is H;

each R_(x) is independently H, C₁-C₆ alkyl, halogen, —OH, —NHS(O)₂R₁₀,or —OC₁-C₆ alkyl; andL₂ is a bond or (CH₂)_(n), wherein n is 1 or 2.

In other embodiments, the compounds of disclosure have the Formula (Ib):

wherein:A, B, C, D, and E are independently N or CR_(x);------- is an optional double bond;

X is CH or C; U is OH or O;

Y and Y′ are independently H, halogen, or C₁-C₆ alkyl;

R₃ is H;

each R_(x) is independently H, C₁-C₆ alkyl, halogen, —OH, —NHS(O)₂R₁₀,or —OC₁-C₆ alkyl; andL₂ is (CH₂)_(n), wherein n is 0, 1 or 2.

In other embodiments of the disclosure the compounds herein describedhave the Formula (Ic):

A, B, C, D, and E are independently N or CR_(x);------- is an optional double bond;

X is CH or C; U is OH or O;

Y and Y′ are independently H, halogen, or C₁-C₆ alkyl;

R₃ is H;

each R_(x) is independently H, C₁-C₆ alkyl, halogen, —OH, —NHS(O)₂R₁₀,or —OC₁-C₆ alkyl; andL₂ is a bond or (CH₂)_(n), wherein n is 1 or 2.

In yet another embodiment, the compounds of the disclosure have theFormula (Id):

wherein:------- is an optional double bond which allows the A ring to bepartially or fully saturated;E is independently N or CR_(x);T is O, S, NR_(y), C═O, or C(R_(x))_(n);V is O, S, N, NR_(y), C═O, or C(R_(x))_(n);each W is independently selected from O, S, C═O, N, NR_(y) orC(R_(x))_(n);

X is CH or C; U is OH or O;

Y and Y′ are independently H, halogen, or C₁-C₆ alkyl;

R₃ is H;

each R_(x) is independently H, C₁-C₆ alkyl, halogen, —OH, or —OC₁-C₆alkyl;R_(y) is H, or C₁₋₆ alkyl;L₂ is a bond or (CH₂)_(n); andeach n is independently 1, or 2.

In another embodiment, illustrative compounds of Formula I include:

In another embodiment of the disclosure, the compounds of Formula I areenantiomers. In some embodiments the compounds are (R)-enantiomer. Inother embodiments the compounds may also be (S)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

Another embodiment of the present disclosure israc-4-(1-hydroxy-2-((3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenolor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure is6-((S)-1-hydoxy-2-((3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure is6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure israc-6-(2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure is6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure is6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure israc-6-(2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Another embodiment of the present disclosure is6-((S)-2-((3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olor a pharmaceutically acceptable salt thereof.

Methods of Using the Disclosed Compounds

In another aspect, the present disclosure is directed to a method oftreating a neurological disease, and abnormal brain function, and/or anemotional disorder in a subject. In some embodiments, the methodcomprises administering to a subject in need thereof an effective amountof a compound according to Formula I including any of the embodiments ofFormula I described herein. The method can also comprise administeringto the subject in need thereof a pharmaceutical composition of acompound of Formula I as described herein.

In an embodiment, the present disclosure pertains to compounds thatselectively modulate the activity of NMDA receptors that contain an NR2Bsubunit, which encompasses receptors containing two NR2B subunits or oneNR2B subunit in combination with one other NR2 subunit (i.e., NR2A/NR2B.NR2B/NR2C, or NR2B/NR2D receptors). The present disclosure also relatesto the therapeutic uses of such compounds.

One therapeutic use of a compound of the present disclosure thatmodulates the activity of NR2B-containing NMDA receptors is to treatpatients suffering from Major Depressive Disorder (MDD, or depression).Depression is the prolonged experience of sadness, hopelessness, orworthlessness to a degree that significantly impairs quality of life andthe ability to function Major Depressive Disorder is now commonlytreated with Selective Serotonin Reuptake Inhibitors (SSRIs) such asProzac, Zoloft and newer variants, but these agents are of limitedeffectiveness. Of additional concern is that even when these drugs areeffective, the onset of action is may be delayed 4-6 weeks or more,during which time patients are at increased risk of suicide.Consequently, the Food and Drug Administration has inserted a black-boxwarning on all antidepressants concerning suicide risk. There is a needfor new agents with greater antidepressant efficacy and faster onset ofaction.

In some embodiments, the neurological disease is selected fromParkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, multiple sclerosis, or seizure disorders.

Another therapeutic use of a compound of the present disclosure thatmodulates the activity of NR2B-containing NMDA receptors is to treatpatients suffering from Alzheimer's disease.

In one or more embodiments, the abnormal brain function is selected fromautism and autism spectrum disorders. Fragile X syndrome, tuberoussclerosis. Down's syndrome or other forms of mental retardation.

The emotional disorder can be selected from bipolar disorder,obsessive-compulsive disorder, or other anxiety disorders. Other anxietydisorders include general anxiety disorder, social anxiety disorder,phobias and panic disorder.

Another therapeutic use for compounds of the present disclosure is inthe treatment of schizophrenia. Schizophrenia is a debilitating mentaldisorder encompassing three symptom domains: positive (hallucination,delusions), negative (withdrawal), and cognitive (pervasive reduction incognitive ability). Schizophrenia typically strikes in early adulthoodwith the emergence of positive symptoms; however, it is the chroniccognitive deficits that prevent patients from resuming normal activitiesafter the initial onset of symptoms and largely accounts for a lifetimedisability.

Given the fundamental role of NR2B containing NMDA receptors in brainfunction (vide supra), there are many other therapeutic uses forcompounds of the present disclosure that modulate the activity ofNR2B-containing NMDA receptors. Compounds of the present disclosure mayimprove cognitive function in individuals suffering from cognitivedeficits in addition to schizophrenia, including but not limited tothose suffering from Alzheimer's disease. Such compounds may also beused in the treatment of post-traumatic stress syndrome. Compounds ofthe present disclosure may be used to treat individuals suffering fromneurological dysfunction, including but not limited to those sufferingfrom Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, multiple sclerosis, and seizure disorders. Compounds of thepresent disclosure may be used to treat individuals suffering fromemotional disorders in addition to depression, including but not limitedto those suffering from bipolar disorder, obsessive-compulsive disorderand other anxiety disorders. Compounds of the present disclosure may beused to treat individuals that experience dysfunction caused by abnormalbrain development, including but not limited to those suffering fromautism and autism spectrum disorders, Fragile X syndrome, tuberoussclerosis, Down's syndrome and other forms of mental retardation. Suchcompounds may also be used to treat abnormal brain function that resultsfrom infections of the central nervous system, exposure to toxic agentsor other xenobiotics or naturally occurring toxins.

Compounds of the present disclosure may also improve cognitivedysfunction such as in Alzheimer's disease, mild cognitive impairment,frontotemporal dementia, multi-infarct dementia, or cognitivedysfunction that occurs after stroke or traumatic brain injury and maybe useful in the treatment of these conditions.

Compounds of the present disclosure may also be useful in treating painsuch as neuropathic pain, pain after nerve or spinal cord injury, painafter tissue damage or burn, or associated pain with diabetes orcardiovascular disease.

Compounds of the present disclosure may also be useful in treatingdepression Depression associated neurodegenerative diseases likeParkinson's (PD) and Alzheimer's disease.

The disclosed compounds can be administered in effective amounts totreat or prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes. Additional modes of administration includesublingual, inhalation and intramuscular.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, aerosol, oral dispersible films or the like, sometimes inunit dosages and consistent with conventional pharmaceutical practices.Likewise, they can also be administered in intravenous (both bolus andinfusion), intraperitoneal, subcutaneous or intramuscular form, and allusing forms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatin and/orHPMC capsules comprising a Compound of the Disclosure and apharmaceutically acceptable carrier, such as a) a diluent, e.g.,purified water, triglyceride oils, such as hydrogenated or partiallyhydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil,sunflower oil, safflower oil, fish oils, such as EPA or DHA, or theiresters or triglycerides or mixtures thereof, omega-3 fatty acids orderivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant.e.g., silica, talcum, stearic acid, its magnesium or calcium salt,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride and/or polyethylene glycol; for tabletsalso; c) a binder, e.g., magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose,magnesium carbonate, natural sugars such as glucose or beta-lactose,corn sweeteners, natural and synthetic gums such as acacia, tragacanthor sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, aliginic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parenteral injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

In accordance with the foregoing, in a further aspect, the disclosurerelates to a compound of the present disclosure for use as a medicament,e. g. for the treatment or prevention of a neurological disease,abnormal brain function or an emotional disorder in which modulation ofNR2B plays a role. In a further embodiment, the disclosure relates to acompound of the present disclosure for use in the treatment of a diseaseor disorder mediated by negative allosteric modulation or inhibition ofNR2B. In a further embodiment, the disease or disorder is majordepressive disorder, refractory and/or treatment resistant depression.In another embodiment the disease or disorder is ADHD. In anotherembodiment the disease or disorder is bipolar disease. In anotherembodiment the disease or disorder is post-traumatic stress disorder. Inanother embodiment the disease or disorder is depression associated witha neurodegenerative disease, such as Parkinson's disease (PD) orAlzheimer's disease (AD). In another embodiment the disease or disorderis neuropathic pain, fibromyalgia, or peripheral neuropathy.

In a further aspect, the disclosure relates to the use of a compound ofthe present disclosure as an active pharmaceutical ingredient in amedicament, e. g. for the treatment or prevention of a neurologicaldisease, abnormal brain function or an emotional disorder in whichmodulation of NR2B plays a role. In a further embodiment, the disclosurerelates to the use of a compound of the present disclosure as an activepharmaceutical ingredient in a medicament for the treatment orprevention of a disease or disorder mediated by negative allostericmodulation or inhibition of NR2B. In a further embodiment the disease ordisorder is major depressive disorder, refractory and/or treatmentresistant depression. In another embodiment the disease or disorder isADHD. In another embodiment the disease or disorder is bipolar disease.In another embodiment the disease or disorder is post-traumatic stressdisorder. In another embodiment the disease or disorder is depressionassociated with a neurodegenerative disease, such as Parkinson's disease(PD) or Alzheimer's disease (AD). In another embodiment the disease ordisorder is neuropathic pain, fibromyalgia, or peripheral neuropathy.

In a further aspect, the disclosure relates to the use of a compound ofthe present disclosure for the manufacture of a medicament for thetreatment or prevention of a neurological disease, abnormal brainfunction or an emotional disorder in which modulation of NR2B plays arole. In a further embodiment, the disclosure relates to the use of acompound of the present disclosure for the manufacture of a medicamentfor the treatment or prevention of a disease or disorder mediated bynegative allosteric modulation or inhibition of NR2B. In a furtherembodiment, the disease or disorder is major depressive disorder,refractory and/or treatment resistant depression. In another embodimentthe disease or disorder is ADHD. In another embodiment the disease ordisorder is bipolar disease. In another embodiment the disease ordisorder is post-traumatic stress disorder. In another embodiment thedisease or disorder is depression associated with a neurodegenerativedisease, such as Parkinson's disease (PD) and Alzheimer's disease (AD).In another embodiment the disease or disorder is neuropathic pain,fibromyalgia, or peripheral neuropathy.

In a further aspect, the disclosure relates to a method for thetreatment or prevention of a neurological disease, abnormal brainfunction or an emotional disorder in which modulation of NR2B plays arole, in a subject in need of such treatment or prevention which methodcomprises administering to such subject an effective amount of acompound of the present disclosure. In one embodiment, the disclosurerelates to a method for the treatment of a disease or disorder mediatedby negative allosteric modulation or inhibition of NR2B in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of a compound of the presentdisclosure. In a further embodiment the disease or disorder is majordepressive disorder, refractory and/or treatment resistant depression.In another embodiment the disease or disorder is ADHD. In anotherembodiment the disease or disorder is bipolar disease. In anotherembodiment the disease or disorder is post-traumatic stress disorder. Inanother embodiment the disease or disorder is depression associated witha neurodegenerative disease, such as Parkinson's disease (PD) andAlzheimer's disease (AD). In another embodiment the disease or disorderis neuropathic pain, fibromyalgia, or peripheral neuropathy.

A compound of the present disclosure can be administered as sole activepharmaceutical ingredient or as a combination with at least one otheractive pharmaceutical ingredient effective, e. g., in the treatment orprevention of a neurological disease, abnormal brain function or anemotional disorder in which modulation of NR2B plays a role. Such apharmaceutical combination may be in the form of a unit dosage form,which unit dosage form comprises a predetermined quantity of each of theat least two active components in association with at least onepharmaceutically acceptable carrier or diluent. Alternatively, thepharmaceutical combination may be in the form of a package comprisingthe at least two active components separately, e. g. a pack ordispenser-device adapted for the concomitant or separate administrationof the at least two active components, in which these active componentsare separately arranged. In a further aspect, the disclosure relates tosuch pharmaceutical combinations.

In a further aspect, the disclosure therefore relates to apharmaceutical combination comprising a therapeutically effective amountof a compound of the present disclosure and a second drug substance, forsimultaneous or sequential administration.

In one embodiment, the disclosure provides a product comprising acompound of the present disclosure and at least one other therapeuticagent as a combined preparation for simultaneous, separate or sequentialuse in therapy. In one embodiment, the therapy is the treatment of adisease or condition in which modulation of NR2B plays a role.

In one embodiment, the disclosure provides a pharmaceutical compositioncomprising a compound of the present disclosure and another therapeuticagent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the disclosure provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of the present disclosure. In one embodiment, the kit comprisesmeans for separately retaining said compositions, such as a container,divided bottle, or divided foil packet. An example of such a kit is ablister pack, as typically used for the packaging of tablets, capsulesand the like. The kit of the disclosure may be used for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit of the disclosure typically comprisesdirections for administration.

In the combination therapies of the disclosure, the compound of thepresent disclosure and the other therapeutic agent may be manufacturedand/or formulated by the same or different manufacturers. Moreover, thecompound of the disclosure and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the disclosure and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the disclosure andthe other therapeutic agent. Accordingly, the disclosure provides anagent of the disclosure for use in the treatment of a disease orcondition in which modulation of NR2B plays a role, wherein themedicament is prepared for administration with another therapeuticagent. The disclosure also provides the use of another therapeutic agentfor treating a disease or condition in which modulation of NR2B plays arole, wherein the medicament is administered with a compound of thepresent disclosure.

The disclosure also provides a compound of the present disclosure foruse in a method of treating a disease or condition in which modulationof NR2B plays a role, wherein the compound of the present disclosure isprepared for administration with another therapeutic agent. Thedisclosure also provides another therapeutic agent for use in a methodof treating a disease or condition in which modulation of NR2B plays arole, wherein the other therapeutic agent is prepared for administrationwith a compound of the present disclosure. The disclosure also providesa compound of the present disclosure for use in a method of treating adisease or condition in which modulation of NR2B plays a role, whereinthe compound of the present disclosure is administered with anothertherapeutic agent. The disclosure also provides another therapeuticagent for use in a method of treating a disease or condition in whichmodulation of NR2B plays a role, wherein the other therapeutic agent isadministered with a compound of the disclosure.

The disclosure also provides the use of an agent of the disclosure fortreating a disease or condition in which modulation of NR2B plays arole, wherein the patient has previously (e.g. within 24 hours) beentreated with another therapeutic agent. The disclosure also provides theuse of another therapeutic agent for treating a disease or condition inwhich modulation of NR2B plays a role, wherein the patient haspreviously (e.g. within 24 hours) been treated with a compound of thedisclosure.

In one embodiment, the disclosure relates to a compound of the presentdisclosure in combination with another therapeutic agent wherein theother therapeutic agent is selected from:

(a) lithium;(b) stimulants, such as amphetamine and dextroamphetamine, (Adderall™)or methylphenidate (Ritalin™);(c) acetylcholinesterase inhibitors, such as donepezil (Aricept™),rivastigmine (Exelon™) and galantamine (Razadyne™);(d) antidepressant medications for low mood and irritability, such ascitalopram (Celexa™), fluoxetine (Prozac™), paroxeine (Paxil™),sertraline (Zoloft™), trazodone (Desyrel™), and tricyclicantidepressants such as amitriptyline (Elavil™);(e) anxiolytics for anxiety, restlessness, verbally disruptive behaviorand resistance, such as lorazepam (Ativan™) and oxazepam (Serax™);(f) antipsychotic medications for hallucinations, delusions, aggression,agitation, hostility and uncooperativeness, such as aripiprazole(Abilify™), clozapine (Clozaril™), haloperidol (Haldol™), olanzapine(Zyprexa™), quetiapine (Seroquel™), risperidone (Risperdal™) andziprasidone (Geodon™);(g) mood stabilizers, such as carbamazepine (Tegretol™) and divalproex(Depakote™);(h) pregabalin;(i) gabapentin (Neurontin™);(j) dopamine agonists such as L-DOPA, pramipexole (Mirapex™) andropinerol (Requip™);(k) analgesics including opiates and non-opiates;(k) carbidopa;(l) triptans such as sumatriptan (Imitrex™) and zolmitriptan (Zornig™);(m) nicotinic apha—7 agonists;(n) mGluR5 antagonists;(o) H3 agonists;(p) amyloid therapy vaccines; and(q) chemotherapy agents.Methods for making theN-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole

Examples of synthetic pathways useful for makingN-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole derivatives ofFormula I, Formula Ia, Formula Ib, Formula Ic, and Formula Id are setforth in the Examples below and generalized in the following Schemes.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

In many examples and intermediates, there is a plane of symmetry presentin the molecules presented resulting in an achiral, meso compound. Thereis, however, relative stereochemistry between groups which is described.For example, (2-((3aR, 5s, 6aS)-5-(3, 4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone) hasa core structure that is designated with absolute configurationdesignations. This nomenclature is used to describe the relativeconfigurations of the aryl ether with respect to the bridgeheadhydrogens. In this example, the substituent is exo with respect to thelarger pyrrolidine ring of the bicyclic system. Conversely,(1-(4-hydroxyphenyl)-2-((3aR,5r,6aS)-5-(4-methoxyphenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone)describes the opposite configuration where the oxygen substituent isendo with respect to the pyrrolidine ring and on the opposite side ofthe bridgehead hydrogens. It is understood that when multiplestereoisomers may exist, all are included within the scope of thedisclosure.

In cases where any substituent also contains a stereogenic center, thecompound becomes chiral and we use the designator “rac” to denote thesynthesis of racemic mixtures of these examples. It is understood thatthe single enantiomers can be separated from this mixture and areincluded within the scope of the disclosure.

LCMS Instrumentation and Methods

Method A Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (50 mm×2.1 mm×1.7 μm)Mobile phase (A): 0.01% TFA in waterMobile phase (B): AcetonitrileFlow rate: 0.3 mL/min

Method B Instrument: Waters 2695

Column: Eclipse XDB-C18 (150 mm×4.6 mm×3.5 μm)Mobile phase (A): 0.01% NH₄OHMobile phase (B): AcetonitrileFlow rate: 1.0 mL/min

Method C Instrument: Waters 2695

Column: Zorbax XDB C18 (150 mm×4.6 mm×3.5 μm)Mobile phase (A): 0.01% NH₄OHMobile phase (B): AcetonitrileFlow rate: 1.0 mL/min

Method D Instrument: Waters 2695

Column: Accentis Express (50 mm×4.6 mm×2.7 μm)Mobile Phase (A): 0.01% Formic acid in water

Mobile Phase (B): Acetonitrile

Flow rate: 0.5 ml/min

Method E Instrument: Agilent 1290 Infinity

Column: Zorbax Eclipse Plus C18 RRHD (50 mm×2.1 mm×1.8 μm)Mobile Phase (A): 0.01% TFA in water

Mobile Phase (B): Acetonitrile

Flow rate: 0.3 mL/min

Method F Instrument: Waters 2695

Column: Gemini (50 mm×3 mm×3 μm)Mobile Phase (A): 0.01% Formic acid in water

Mobile Phase (B): Acetonitrile

Flow rate: 0.5 ml/min

Method G Instrument: Waters 2695

Column: Gemini C18 (50 mm×3.0 mm×3 μm)Mobile Phase (A): 0.01% TFA in water

Mobile Phase (B): Acetonitrile

Flow rate: 0.5 ml/min

Method H Instrument: Waters 2695

Column: XTERRA C18 (250 mm×4.6 mm×5 μm)Mobile phase (A): Ammonia in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL/min

Method I Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (50 mm×2.1 mm×2.6 μm)Mobile phase (A): 0.01% acetic acid in waterMobile phase (B): AcetonitrileFlow rate: 0.3 mL/min

Method J Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (100 mm×4.6 mm×2.1 μm)Mobile phase (A): 0.01% TFA in waterMobile phase (B): AcetonitrileFlow rate: 0.7 mL/min

Method K Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (100 mm×4.6 mm×2.6 μm)Mobile phase (A): 0.01% TFA in waterMobile phase (B): AcetonitrileFlow rate: 0.7 mL/min

Method L Instrument: Agilent 1290 Infinity

Column: Denali C18 (50 mm×2.1 m×5 μm)Mobile phase (A): 0.01% NH4OHMobile phase (B): AcetonitrileFlow rate: 0.7 mL/min

Method M Instrument: Agilent 1290 Infinity

Column: Zorbax RRHD C18 (50 mm×2.1 mm×1.8 μm)Mobile phase (A): 0.01% Acetic acid in waterMobile phase (B): AcetonitrileFlow rate: 0.3 mL/min

Method N Instrument: Waters 2695

Column: Xbridge C18 (250 mm×4.6 mm×5 μm)Mobile phase (A): 0.01% TFA in waterMobile phase (B): AcetonitrileFlow rate: 1.0 mL/min

Method O Instrument: Waters 2695

Column: Ascentis Express C18 (50 mm×2.1 mm×2.7 μm)Mobile phase (A): 0.01% Formic acid in waterMobile phase (B): AcetonitrileFlow rate: 0.5 mL/min

Method P Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (50 mm×2.1 mm×1.7 μm)Mobile phase (A): WaterMobile phase (B): AcetonitrileFlow rate: 0.3 mL/min

Method Q Instrument: Agilent 1290 Infinity

Column: Kinetex C18 (50 mm×2.1 mm×1.7 μm)Mobile phase (A): 5 mM Ammonium acetate in waterMobile phase (B): AcetonitrileFlow rate: 0.3 mL/min

Method R Instrument: Waters Acquity SDS

Run time: 5.20 minColumn: ACQUITY UPLC BEH C18, 130 Å, 1.7 m, 2.1 mm×50 mm−50° C.Mobile phase (A): Water+0.1% formic acidMobile phase (B): Acetonitrile+0.1% formic acid

Method S Preparative SFC Column: AD-H 250×21 mm

Flow rate: 80 g per minute

Cosolvent: 35% EtOH 10 mM NH₄OH Detection: 207 nm ABPR 100 Example1—Preparation ofrac-4-(2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol

Compound 1 can be purchased from a commercial vender. It can also besynthesized based on Scheme 1, PCT Int. Appl. 2014048865 or PCT Int.Appl. 2013091539.

Step 1 Preparation of (3aR,5r,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.5 g, 36.63 mmol)in ethanol (300 mL) was added sodium borohydride (11.8 g, 310.52 mmol))at 0° C. The reaction mixture was stirred at room temperature for 3 hand concentrated. The residue was diluted with water (300 mL) andextracted with dichloromethane (500 mL×3). The combined organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude material was purified by chiral HPLC column chromatography(analytical conditions: column: CHIRALPAK IA (250 mm×4.6 mm×5 μm),mobile phase: n-Hexane: 0.1% DEA in ethanol (50:50), Flow rate: 1.0mL/min) to afford title compound (3aR,5r,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (7.2 g, 75%yield, major isomer 2) as a white solid. Calculated M+H: 262.32; FoundM+H: 262.1.

During purification the minor isomer 2A (3aR,5s,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.65 g, 6.8%yield) was also isolated as a colourless liquid.

A crystallization method was used to separate the major isomer fromminor isomer. Ethyl acetate (180 mL) was added portion wise to a mixtureof diasteriomers (42 g, 16.09 mmol) in hexane (400 mL) at 75° C. Themixture was heated at same temperature with stirring until all of thesolid dissolved. Then the mixture was concentrated at 75° C. to onethird of the initial volume, seeded with authentic product and kept forrecrystallisation at room temperature for 15 h. The crystallized productwas filtered, washed with 20% ethyl acetate in hexane (200 mL) and driedto afford the title compound 2 (36 g, 98.5% chiral purity) as a whitesolid. This material was again recrystallised from ethyl acetate-hexaneusing above condition to afford the title compound (3aR,5r,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (34 g, 99.5%chiral purity) as a white solid.

Step 2 Preparation of (3aR,5s,6aS)-benzyl5-(3,4-Difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,5r,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.6 g, 2.298mmol) in tetrahydrofuran (20 mL) at 0° C. were added 3,4-difluorophenol(0.6 g, 4.59 mmol), triphenylphosphine (0.66 g, 2.528 mmol) and diethylazo dicarboxylate (0.54 mL, 3.44 mmol). The reaction mixture was stirredat room temperature for 18 h and concentrated. Then crude was purifiedby combiflash purifier using 20-25% ethyl acetate in hexane to affordthe title compound (3aR,5s,6aS)-benzyl5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.34 g, 39.67% yield) as a pale yellow liquid. Calculated M+H: 374.39;Found M+H: 374.2.

Step 3 Preparation of (3aR, 5s, 6aS)-5-(3, 4-difluorophenoxy)octahydrocyclopenta[c]pyrrole

To a solution of(3aR,5s,6aS)-benzyl-5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.34 g, 0.911 mmol) in ethanol (5 mL) was added 10% Pd/C (0.1 g, 50%wet). The reaction mixture was stirred at room temperature for 3 h underhydrogen atmosphere. The suspension was filtered through celite and thebed was washed with methanol. The combined filtrate was concentrated toafford the title compound (3aR, 5s, 6aS)-5-(3,4-difluorophenoxy)octahydrocyclopenta[c]pyrrole (0.2 g, crude) as a colorless liquid.Calculated M+H: 240.26; Found M+H: 240.1.

Step 4 Preparation of 2-((3aR, 5s, 6aS)-5-(3, 4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone

To a solution of (3aR,5s,6aS)-5-(3.4-difluorophenoxy)octahydrocyclopenta[c]pyrrole (0.2 g,0.878 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.36g, 2.63 mmol) followed by 2-bromo-1-(4-hydroxyphenyl) ethanone (0.18 g,0.878 mmol). The resulting suspension was stirred at room temperaturefor 3 h. The reaction mixture was filtered and the filtrate wasconcentrated. The crude was purified by combiflash purifier using 3%methanol in dichloromethane to afford the title compound2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone(0.28 g, 85.36% yield) as a white solid. Calculated M+H: 374.39; FoundM+H: 374.2.

Step 5 Preparation of rac-4-(2-((3aR, 5s, 6aS)-5-(3, 4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl) phenol

To a solution of 2-((3aR,5s,6aS)-5-(3, 4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone(0.25 g, 0.672 mmol) in ethanol (5 mL) was added sodium borohydride(0.25 g, 6.72 mmol)) at 0° C. The reaction mixture was stirred at roomtemperature for 3 h and concentrated. The residue was diluted with water(50 mL) and extracted with dichloromethane (100 mL×2). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by combiflash purifier using 4%methanol in dichloromethane to afford the title compoundrac-4-(2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl) phenol (0.12 g,48.0% yield) as a white solid. Calculated M+H: 376.41; Found M+H: 376.2.

Example 2—Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone

Alternative α-halo ketones for use in step 4 above were prepared by thefollowing methods

Step 1 Preparation of 5-hydroxypicolinoyl chloride

To a suspension of 5-hydroxypicolinic acid (1.0 g, 7.18 mmol) indichloromethane (70 mL) and catalytic N,N-dimethyl formamide (0.2 mL),was added oxalyl chloride (1.25 mL, 14.37 mmol) slowly at 0° C., theresulting suspension was allowed to warm to room temperature andrefluxed for 16 h. The mixture was allowed to cool to room temperatureand concentrated under vacuum to afford the title compound5-hydroxypicolinoyl chloride (1.1 g, crude) which was as such taken fornext step without further purification.

Step 2 Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone

To a suspension of 5-hydroxypicolinoyl chloride (1.1 g, 7.18 mmol,crude) in dichloromethane:tetrahydrofuran mixture (1:1, 50 mL) was addedtrimethyl silyl diazomethane (9.5 mL, 19.04 mmol, 2M in hexane) slowlyat 0° C., and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was cooled to 0° C., and aqueous hydrobromicacid (47%, 3 mL, 19.04 mmol) was added. The reaction mixture was allowedwarm to room temperature and stirred for 2 h. The solid formed wasfiltered, the washed with dichloromethane, diethyl ether and dried toobtain the title compound 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone (0.6g, crude) as pale brown solid. Calculated M+H: 215.96; Found M+H: 216.0.

Example 3—Preparation of 2-bromo-1-(3-fluoro-4-hydroxyphenyl) ethanone

To a suspension of 1-(3-fluoro-4-hydroxyphenyl) ethanone (2.0 g, 12.98mmol) in 33% hydrobromic acid in acetic acid (200 mL), was added asolution of bromine (0.53 mL, 10.389 mmol) in 20 mL of 33% hydrobromicacid in acetic acid at 0° C., and stirred at the same temperature for 3h. The reaction mixture was diluted with ice water (100 mL) and extractwith ethyl acetate (100 mL×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 3% ethyl acetate inhexane to afford the title compound 2-bromo-1-(3-fluoro-4-hydroxyphenyl)ethanone (1.5 g, 49.66% yield) as a white solid. Calculated M+H: 232.95;Found M+H: 233.0.

Example 4—Preparation of2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone

Step-1 Preparation of 6-bromo-2-fluoropyridin-3-ol

To a solution of 2-fluoropyridin-3-ol (1 g, 8.842 mmol) and sodiumacetate (0.72 g, 8.842 mmol) in acetic acid (10 mL) was added bromine(0.23 mL, 8.842 mmol) at 0° C., and the reaction mixture was stirred atroom temperature for 4 h. The solution was poured into ice, pH wasadjusted to 6 using 2N sodium hydroxide solution and extracted withethyl acetate (50 mL×2). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the crudeproduct, which was purified by silica gel column chromatography (10%ethyl acetate/hexane) to obtain the title compound6-bromo-2-fluoropyridin-3-ol (0.5 g, 30% yield) as a colorless liquid.Calculated (M+H): 193; Found (M+1): 193.9

Step-2 Preparation of6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine

To a solution of 6-bromo-2-fluoropyridin-3-ol (0.5 g, 2.604 mmol) intetrahydrofuran (20 mL) was added triethylamine (0.54 mL, 3.906 mmol)and the reaction mixture was cooled to 0° C. Chlorotriisopropylsilane(0.73 mL, 3.385 mmol) was added drop wise and the solution was stirredat room temperature for 2 h. The reaction mixture was diluted with water(30 mL) and extracted with ethyl acetate (50 ml×2). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto afford the crude product, which was purified by silica gel columnchromatography (5% ethyl acetate/hexane) to obtain the title compound6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine (0.8 g, 87% yield)as a colorless liquid. Calculated (M+H): 348.07; Found (M+1): 348.1.

Step-3 Preparation of6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine

To a solution of 6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine(0.4 g, 1.148 mmol) and tributyl(1-ethoxyvinyl)stannane (0.43 mL, 1.263mmol) in toluene argon was purged for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) was added and the reactionmixture was heated at 100° C. for 18 h. The solution was filteredthrough celite and filtrate was concentrated to afford the titlecompound 6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine(0.36 g, crude) as brownish gum. Calculated (M+H): 340.5; Found (M+1):340.2

Step-4 Preparation of 2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone

To a solution of6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine (8.46 g,24.93 mmol) in tetrahydrofuran:water (280 ml, 3:1) mixture was addedN-bromosuccinimide and the reaction mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with water (150mL) and extracted with ethyl acetate (300 mL×2). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto afford the crude product, which was purified by silica gel columnchromatography (40% ethyl acetate/hexane) to obtain the title compound2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone (5.5 g, 95% yield) asbrownish gum. Calculated (M+H): 235.02; Found (M+1): 235.9

These α-halo ketones were used in Steps 4 and 5 of Example 1 to preparethe following compounds.

TABLE 1 Compounds prepared using the α-halo ketones of Examples 2-4.Calcu- Retention lated Found time Structure IUPAC Name M + H M + H (min)Method

1-(4-hydroxyphenyl)- 2-((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 339.4 339.2 1.392 G

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)phenol 341.42 341.2 4.719H

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 357.39 357.1 1.165 I

rac-2-fluoro-4-(1- hydroxy-2- ((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)phenol 359.41 359.92 0.915A

1-(5-hydroxypyridin- 2-yl)-2-((3aR,5s,6aS)- 5-(3- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 369.43 369.5 1.953 A

rac-6-(1-hydroxy-2- ((3aR,5s,6aS)-5-(3- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)pyridin-3-ol 371.44 371.51.699 A

1-(6-fluoro-5- hydroxypyridin-2-yl)- 2-((3aR,5s,6aS)-5-(4-fluorophenoxy) hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)ethanone 375.38375.1 2.038 A

rac-2-fluoro-6-(2- ((3aR,5s,6aS)-5-(4- fluorophenoxy)hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol377.39 377.4 1.99 A

1-(4-hydroxyphenyl)- 2-((3aR,5s,6aS)-5-((6- methylpyridin-3- yl)oxy)hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)ethanone 353.43 353.2 1.163 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5-((6- methylpyridin-3- yl)oxy)hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)ethyl)phenol 355.45 355.2 7.816C

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5-((6- methylpyridin-3-yl)oxy) hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)ethanone 371.41 371.41.184 A

rac-2-fluoro-4-(1- hydroxy-2- ((3aR,5s,6aS)-5-((6- methylpyridin-3-yl)oxy) hexahydrocycopenta [c]pyrrol- 2(1H)-yl)ethyl)phenol 373.43 373.21.077 A

2-((3aR,5s,6aS)-5-(4- fluorophenoxy) hexahydrocyclopenta [c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 357.39 357.2 1.593 G

rac-6-(2- ((3aR,5s,6aS)-5-(4- fluorophenoxy) hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol 359.40 359.2 2.697 J

1-(4-hydroxyphenyl)- 2-((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 368.44 368.2 1.934 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)phenol 370.45 370.2 1.942A

1-(5-hydroxypyridin- 2-yl)-2-((3aR,5s,6aS)- 5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 369.43 369.5 1.953 A

rac-6-(1-hydroxy-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)pyridin-3-ol 371.44 371.51.668 A

1-(5-hydroxy-6- methoxypyridin-2-yl)- 2-((3aR,5s,6aS)-5-(4-methoxyphenoxy) hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 399.45399.2 1.986 A

rac-6-(1-hydroxy-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)-2- methoxypyridin-3-ol401.47 401.5 1.841 A

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 386.43 386.5 2.033 A

rac-2-fluoro-4-(1- hydroxy-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)phenol 388.44 388.5 1.929A

1-(6-fluoro-5- hydroxypyridin-2-yl)- 2-((3aR,5s,6aS)-5-(4-methoxyphenoxy) hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethanone 385.42(M − H) 385.2 (M − 1H) 2.062 A

rac-2-fluoro-6-(1- hydroxy-2- ((3aR,5s,6aS)-5-(4- methoxyphenoxy)hexahydrocyclopenta [c]pyrrol-2(1H)- yl)ethyl)pyridin-3-ol 389.43 389.51.913 A

2-((3aR,5s,6aS)-5- (3,4- difluorophenoxy) hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-1-(5- hydroxypyridin-2- yl)ethanone 375.38 375.12.779 A

rac-6-(2- ((3aR,5s,6aS)-5-(3,4- difluorophenoxy) hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-1-hydroxyethyl) pyridin-3-ol 377.4 377.2 1.535 G

4-(((3aR,5s,6aS)-2-(2- (5-hydroxypyridin-2- yl)-2-oxoethyl)octahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile 364.41 364.5 1.856A

rac-4-(((3aR,5s,6aS)- 2-(2-hydroxy-2-(5- hydroxypyridin-2- yl)ethyl)octahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile 366.43 366.5 1.614A

4-(((3aR,5s,6aS)-2-(2- (6-fluoro-5- hydroxypyridin-2-yl)- 2-oxoethyl)oetahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile 382.4 382.3 1.917 A

rac-4-(((3aR,5s,6aS)- 2-(2-(6-fluoro-5- hydroxypyridin-2-yl)-2-hydroxyethyl) octahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile384.42 384.2 1.82 A

4-(((3aR,5s,6aS)-2-(2- (4-hydroxyphenyl)-2- oxoethyl)octahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile 363.42 363.2 1.969A

rac-4-(((3aR,5s,6aS)- 2-(2-hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta [c]pyrrol-5- yl)oxy)benzonitrile 365.44 365.2 1.92 A

2-((3aR,5s,6aS)-5- (3,5-difluorophenoxy) hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-1-(5- hydroxypyridin- 2-yl)ethanone 375.38 375.41.481 C

rac-6-(2- ((3aR,5s,6aS)-5-(3,5- difluorophenoxy) hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol 377.4 377.4 1.542 G

2-((3aR,5s,6aS)-5-((5- chloropyridin-3- yl)oxy) hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl) ethanone 373.85 373.3 1.835 A

rac-4-(2- ((3aR,5s,6aS)-5-((5- chloropyridin-3- yl)oxy)hexahydrocycopenta [c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 375.86375.2 1.7 A

rac-4-(2- ((3aR,5s,6aS)-5-((5- fluoropyridin-3- yl)oxy)hexahydrocyclopenta [c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 359.41359.2 1.549 A

2-((3aR,5s,6aS)-5-(4- fluorophenoxy) hexahydrocyclopenta [c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl) ethanone 356.40 356.17 N/A N/A

rac-2-((3aR,5s,6aS)-5- (4-fluorophenoxy) hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-1-(4- hydroxyphenyl) ethanol 358.42 358.25 N/A N/A

The minor isomer 2A from step 1 can also be used to create compoundswith the opposite relative configuration as shown in the followingexamples.

Example 6—Preparation of (3aR,5r,6aS)-benzyl5-(4-methoxyphenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,5s,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.7 g, 6.51mmol) in tetrahydrofuran (12 mL) at 0° C. were added 4-methoxyphenol(0.81 g, 6.51 mmol), triphenylphosphine (1.87 g, 7.16 mmol) and diethylazo dicarboxylate (1.53 mL, 9.76 mmol). The reaction mixture was heatedat 60° C. in microwave for 2 h and concentrated. Then crude was purifiedby combiflash purifier using 15% ethyl acetate in dichloromethane toafford the title compound 17 (3aR,5r,6aS)-benzyl5-(4-methoxyphenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.02 g, 42.0% yield) as a brownish liquid. Calculated M+H: 368.44;Found M+H: 368.2.

17 can be elaborated by the method used to prepare Steps 4 and 5 ofExample 1 and the ketones of Examples 2-4 to afford1-(4-hydroxyphenyl)-2-((3aR,5r,6aS)-5-(4-methoxyphenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanoneandrac-4-(1-hydroxy-2-((3aR,5r,6aS)-5-(4-methoxyphenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol(Table 2). Additional compounds prepared by these procedures aredescribed in Table 2.

TABLE 2 Analogs prepared from 2A. Retention Calculated Found timeStructure IUPAC Name M + H M + H (min) Method

1-(4-hydroxyphenyl)-2- ((3aR,5r,6aS)-5-(4- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethanone 368.44 368.2 1.956 A

rac-4-(1-hydroxy-2- ((3aR,5r,6aS)-5-(4- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethyl)phenol 370.42 370.2 1.82 A

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5r,6aS)-5-(4-methoxyphenoxy)hexahy- drocyclopenta[c]pyrrol- 2(1H)-yl)ethanone 386.43386.2 2.031 A

rac-2-fluoro-4-(1- hydroxy-2-((3aR,5r,6aS)- 5-(4- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethyl)phenol 388.44 388.2 1.921 A

1-(5-hydroxypyridin-2- yl)-2-((3aR,5r,6aS)-5-(4- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethanone 369.43 369.2 2.067 A

rac-6-(1-hydroxy-2- ((3aR,5r,6aS)-5-(4- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethyl)pyridin-3- ol 371.44 371.2 1.738A

4-(((3aR,5r,6aS)-2-(2-(5- hydroxypyridin-2-yl)-2-oxoethyl)octahydrocyclopen- ta[c]pyrrol-5- yl)oxy)benzonitrile 364.41364.4 1.905 A

rac-4-(((3aR,5r,6aS)-2- (2-hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclopen- ta[c]pyrrol-5- yl)oxy)benzonitrile 366.43366.2 1.61 A

Example 7—Preparation ofrac-4-(2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol

An alternative synthetic route was used to prepare the other examples.

Step 1 Preparation of (3aR,5s,6aS)-benzyl 5-((methylsulfonyl) oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR, 5r, 6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.1 g, 11.87mmol) in dichloromethane (30 mL) was added triethylamine (3 mL, 23.74mmol) at room temperature. The reaction mixture was cooled to 0° C., andmethanesulfonyl chloride (2.03 g, 17.82 mmol) was slowly added. Theresultant mixture was allowed to warm to room temperature and stirredfor 3 h. The solution was quenched with saturated ammonium chloridesolution (25 mL) and extracted with dichloromethane (200 mL×3). Thecombined extracts were washed with brine solution (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound (3aR, 5s, 6aS)-benzyl 5-((methylsulfonyl) oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3 g, 75%) as acolorless liquid. Calculated M+H: 340.41; Found M+H: 340.1.

Step 2 Preparation of (3aR,5s,6aS)-benzyl 5-(2-fluoropyridine)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR, 5s, 6aS)-benzyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.7 g, 2.064 mmol) inacetonitrile (15 mL), 2-fluoropyridine-3-ol (0.349 g, 3.097 mmol) andcesium carbonate (1.353 g, 4.128 mmol) were added at room temperatureand the reaction mixture was stirred at 80° C. for 4 h. The reactionmixture was concentrated, the residue was diluted with water (100 mL)and extracted with ethyl acetate (200 mL×2). The combined organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified by combiflash purifier using 20-25% ethyl acetate inhexane to afford the title compound (3aR,5s,6aS)-benzyl5-(2-fluoropyridine) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.8 g, crude) as a pale yellow liquid. Calculated M+H: 357.16; FoundM+H: 357.2.

Step 3 Preparation of (3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)octahydrocyclopenta[c]pyrrole

To a solution of (3aR, 5s, 6aS)-benzyl 5-(2-fluoropyridine)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.8 g, 1.40 mmol) inethanol (40 mL) was added 10% Pd/C (50% wet) (0.4 g) and the reactionmixture was stirred at room temperature for 3 h under hydrogenatmosphere. The reaction mixture was filtered through celite and washedwith methanol. The combined filtrate was concentrated and dried toafford the title compound (3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)octahydrocyclopenta[c]pyrrole (0.4 g, crude) as a colorless liquid.Calculated M+H: 223.26; Found M+H: 223.3.

Step 4 Preparation of 2-((3aR, 5s, 6aS)-5-((2-fluoropyridin-3-yl) oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone

To a solution of (3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)octahydrocyclopenta[c]pyrrole (0.3 g, 1.35 mmol) in acetonitrile (10 mL)was added triethylamine (0.58 mL, 4.053 mmol) followed by2-bromo-1-(4-hydroxyphenyl) ethanone (0.232 g, 1.081 mmol) and theresulting suspension was stirred at room temperature for 3 h. Thereaction mixture was concentrated, the residue was diluted with water(50 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by combiflash purifier using 2-3%methanol in dichloromethane to afford the title compound2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone (0.13 g, 27% yield) as a white solid. Calculated M+H: 357.4;Found M+H: 357.2

Step 5 Preparation of rac-4-(2-((3aR, 5s,6aS)-5-(2-fluoropyridin-3-yl)oxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl) phenol

To a solution of 2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl) oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ethanone(0.15 g, 0.421 mmol) in methanol (10 mL) was added sodium borohydride(0.15 g, 4.21 mmol) at 0° C., and the suspension was stirred at roomtemperature for 3 h. The reaction mixture was concentrated; the residuewas diluted with water (50 mL) and extracted with dichloromethane (100mL×2). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified by combiflashpurifier using 4% methanol in dichloromethane to afford the titlecompound4-(2-((3aR,5s,6aS)-5-(2-fluoropyridin-3-yl)oxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol (0.10 g, 66.0% yield) as a white solid. Calculated M+H: 359.41;Found M+H: 359.2.

Example 8—Preparation of6-((S)-1-hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol

Step 1 Preparation of benzyl(3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of benzyl (3aR,5r,6aS)-5((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(30.35 g, 90 mmol) in 600 mL of acetonitrile was added phenol (9.27 g,98 mmol) and cesium carbonate (58.3 g, 179 mmol). The mixture wasstirred with heating at 65° C. for two hours and filtered through a padof Celite. The Celite was washed with acetonitrile. The filtrate wascombined and concentrated. The residue was chromatographed twice onsilica gel eluting with heptane/ethyl acetate to afford 20.15 g (67%) ofbenzyl(3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate.LCMS [M+H]⁺338.3, 1.35 min, method R.

Step 2 Preparation of(3aR,5s,6aS)-5-phenoxyoctahydrocyclopenta[c]pyrrole

To a stirred suspension of benzyl(3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(20.08 g, 59.6 mmol) in 700 mL of ethanol was added 2.9 g of 10%palladium on carbon (wet degussa type). The mixture was degassed, purgedand exposed to one atmosphere of hydrogen gas for 1 hour. Another 2.7 gof 10% palladium on carbon was added and the reaction mixture wasstirred for an hour. The catalyst was filtered with the aid of wetethanol and the filtrate was concentrated to afford 12.23 g (100%) of(3aR,5s,6aS)-5-phenoxyoctahydrocyclopenta[c]pyrrole. LCMS [M+H]⁺ 204.3,0.84 min, method R.

Step 3 Preparation of1-(5-hydroxypyridin-2-yl)-2-((3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one

Two independent solutions of2-bromo-1-(5-hydroxypyridin-2-yl)ethan-1-one (8.75 g, 29.6 mmol) in 30mL of DMF and (3aR,5s,6aS)-5-phenoxyoctahydrocyclopenta[c]pyrrole (8.22g. 40.5 mmol) in 40 mL of DMF/2-methyltetrahydrofuran (1:3) were addedseparately at the same rate to a stirring solution of triethylamine(3.09 mL, 22.18 mmol) in 20 mL of 2-methyltetrahydrofuran in an ice bathover 1 hour. After 1.5 hours of stirring from the start of the addition,the reaction mixture was quenched with saturated potassium dihydrogenphosphate solution. The aqueous layer was extracted withdichloromethane. The organic layer was washed with brine, dried(Na₂SO₄), filtered through a pad of florisil with the aid of ethylacetate-ethanol and concentrated to an orange oil. The oil waschromatographed on silica gel eluting with dichloromethane-ethylacetate-EtOH.

Brine was added to the aqueous phosphate solution. It was extracted withethyl acetate, The organic layer was dried (N₂SO₄) and filtered througha pad of florisil with the aid of ethyl acetate-EtOH. The organicsolution was concentrated until crystallization was observed. The solidwas collected by filtration and dried. In combination 7.19 g (72%) of1-(5-hydroxypyridin-2-yl)-2-((3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-onewas obtained. LCMS [M+H]⁺ 339.3, 1.13 min, method R.

Step 4 Preparation of6-((S)-1-hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol

To a stirred nitrogen-flushed solution of1-(5-hydroxypyridin-2-yl)-2-((3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one(7.19 g, 21.27 mmol) and RuCl(p-cymene)[(S,S)-TsDPEN] (0.541 g, 0.851mmol) in 100 mL of DMF was added a solution of formic acid (4.01 mL, 106mmol) and triethylamine (5.94 mL, 42.5 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction was quenched withaqueous NaHCO₃ solution. Ethyl acetate was added and the organic phasewas washed with brine, dried (Na₂SO₄) and filtered. The filtrate waspassed through a pad of florisil with the aid of ethyl acetate-ethanoland concentrated. The residue was then chromatographed on silica geleluting with MeOH-DCM and concentrated until crystallization wasobserved. The solid was collected by filtration, washed with heptane,ether, and dried. Concentration of the filtrate afforded another crop,which was combined to afford 5.15 g of6-((S)-1-hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-olas a solid. The solid was further purified by preparative SFC (methodS). The obtained methanolic solution was treated with 400 mg ofSi-Triamine scavenger reagent for over 8 hours, filtered andconcentrated to afford 4.07 g (80%) of6-((S)-1-hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol.Purity was >98% and Ruthenium level was found to be 54 ppm. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.66 (dt, J=12.75, 4.75 Hz, 2 H) 1.83-1.94 (m, 2 H)2.30 (dt, J=8.74, 6.69 Hz, 2H) 2.52-2.60 (m, 4 H) 2.65 (dd, J=12.10,5.01 Hz, 1H) 4.60 (dd, J=7.34, 5.14 Hz, 1H) 4.80 (quin, J=4.62 Hz, 1H)4.99 (br s, 1 H) 6.82-6.91 (m, 3H) 7.13 (dd, J=8.56, 2.81 Hz, 1H)7.23-7.31 (m, 3H) 8.03 (d. J=2.45 Hz, 1 H) 9.67 (br s, 1H); LCMS [M+H]⁺341.4, 0.91 min, method R

The absolute stereochemistry was confirmed by x-ray crystallography(FIG. 1).

Example 9—Preparation of6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol

Step 1 Preparation of6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol

To a stirred nitrogen-flushed solution of1-(5-hydroxypyridin-2-yl)-2-((3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one(0.20 g, 0.59 mmol) and RuCl(p-cymene)[(R,R)-TsDPEN] (0.015 g, 0.024mmol) in 15 mL of DMF was added a solution of formic acid (0.112 mL,2.96 mmol) and TEA (0.165 mL, 1.18 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction was quenched withaqueous NaHCO₃ solution. Ethyl acetate was added and the organic phasewas washed with brine, dried (Na₂SO₄) and filtered. The filtrate waspassed through a pad of florisil with the aid of ethyl acetate-ethanoland concentrated. The residue was purified by preparative SFC (method S)to afford 71 mg (35%) of6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol.¹H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.02 (d, J=2.5 Hz, 1H),7.55-7.20 (m, 3H), 7.13 (dd. J=2.8, 8.5 Hz, 1H), 6.97-6.76 (m, 3H), 5.00(s, 1H), 4.81 (p, J=4.6 Hz, 1H), 4.60 (t, J=5.6 Hz, 1H), 2.79-2.44 (m,5H), 2.44-2.18 (m, 2H), 2.04-1.79 (m, 2H), 1.66 (dt, J=4.6, 12.7 Hz,2H); LCMS [M+H]⁺ 341.3, 0.92 min, method R.

Example 10—Preparation of6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol

Step 1 Preparation of benzyl(3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred suspension of potassium carbonate (26.9 g, 194 mmol) inMeCN (Volume: 400 mL) was added 2-fluorophenol (7.89 mL, 88 mmol). Thereaction mixture was stirred at room temperature for 15 minutes, then tothis was added benzyl(3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(30 g, 88 mmol) as a solid. The suspension was stirred at roomtemperature for 10 minutes and heated at 60° C. overnight and then anadditional 6 hours. The reaction was diluted with additionalacetonitrile (200 mL) and heated overnight. The suspension was allowedto cool to room temperature and filtered over Celite plug. The filtratewas partially evaporated and diluted with EtOAc (200 mL) and water (200mL). The organic layer was washed with saturated NaHCO₃ solution, driedover MgSO₄, filtered and concentrated. The residue was loaded onto a 750g Redisep column and eluted with n-heptane:EtOAc gradient (0-40%).Fractions were collected, combined and evaporated to give a pale yellowoil, which crystallized on standing to give benzyl(3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(22.6 g; 72% yield). LC-MS: [M+H]⁺ 356.3, Rt=1.88 min, method R.

Step 2 Preparation of(3aR,5s,6aS)-5-(2-fluorophenoxy)octahydrocyclopenta[c]pyrrole

To a stirred solution of benzyl(3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(22.6 g, 60.5 mmol) in ethanol (Volume: 400 mL) under nitrogen wascharged 10% palladium on carbon (wet—degussa) (0.644 g. 0.605 mmol; 10mol %). The stirred suspension was then placed under a balloon ofhydrogen gas (several evacuation/charging phases completed) and then wasallowed to stir at room temperature for 2 hours. The reaction mixturewas placed under N₂ atmosphere. The catalyst was removed via suctionfiltration over Celite plug, and the filtrate was concentrated in vacuoto give (3aR,5s,6aS)-5-(2-fluorophenoxy)octahydrocyclopenta[c]pyrrole asa pale yellow oil (14.2 g; 100% yield). LC-MS: [M+H]⁺ 222.2 Rt=0.85 min,method R.

Step 3 Preparation of2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethan-1-one

Solution A:(3aR,5s,6aS)-5-(2-fluorophenoxy)octahydrocyclopenta[c]pyrrole (9.48 g,42.9 mmol) and triethylamine (3.45 ml, 24.74 mmol) in DMF (45 mL).Solution B: 2-bromo-1-(5-hydroxypyridin-2-yl)ethan-1-one (9.5 g, 33.0mmol) in DMF (45 mL).

Solution A and Solution B were pumped together (at 1.0 m/min) mixing ata T-piece mixer, followed by a 10 ml reaction loop (total residence time5 min), and output was collected into a stirred reaction vial containingdichloromethane and 10% KH₂PO₄ solution. The biphasic solution wasseparated, and the organic layer was dried over Na₂SO₄, evaporated underhigh vacuum to remove as much solvent as possible without heating waterbath above 20° C. The dark orange/brown solution was then loaded onto alarge dry silica plug, and washed with DCM, followed by elution througha 750 g Redisep column using a DCM/[EtOAc/EtOH (3:1)] gradient column togive2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethan-1-oneas an orange foam (6.7 g). LC-MS: [M+H]⁺ 357.3, Rt=1.08 min, method R.

Step 4 Preparation of6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol

2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-5-hydroxypyridin-2-yl)ethan-1-one(6.7 g, 18.8 mmol) in DMF (Volume: 94 ml) was de-gassed under N₂ flowfor 10 minutes. The reaction mixture was charged with a preformedmixture of formic acid (3.55 ml, 94 mmol) and triethylamine (5.24 ml,37.6 mmol). This was then followed by catalystRuCl(p-Cymene)-[(S,S-pTs-DPEN)] (0.359 g, 0.564 mmol), and reaction wasallowed to stir at room temperature under inert N₂ atmosphere. After 16hours additional catalyst was added (1 mol %) (total 4 mol % added forreaction) and the reaction was stirred for an additional 7 hours. Thereaction was quenched with saturated NaHCO₃ solution and diluted withEtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated (40° C. water bath) to a dark brown crude residue, whichwas loaded directly onto dry silica (as DMF concentrate) and eluted downa 330 g Redisep column with DCM/MeOH (0-30%) to yield a pale greensolid. The solid was taken up in refluxing methyl tert-butyl either(MTBE), and was hot filtered. The filtrate was treated with charcoal,filtered and evaporated to give a solid. The solid was taken back up inhot MTBE (150 ml), followed by addition of n-heptane (150 mL), and wasrecrystallized overnight, which upon filtration and washing withn-heptane yielded an off-white solid. The solid was dried in a vacuumoven for 3 days (at 40° C.) to give6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol(3.38 g). ¹H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.13-7.87 (m, 1H),7.29 (d, J=8.5 Hz. 1H), 7.22-7.00 (m, 4H), 7.00-6.77 (m, 1H), 4.99 (s,1H), 4.84 (q, J=4.4 Hz, 1H), 4.60 (s, 1H), 2.77-2.40 (m, 5H), 2.39-2.20(m, 2H), 1.93 (dd, J=4.3, 8.8 Hz, 2H), 1.65 (dt, J=4.8, 13.0 Hz, 2H).LC-MS: [M+H]⁺ 359.4 Rt=0.93 min, method R.

The absolute stereochemistry was confirmed by x-ray crystallography(FIG. 2).

Example 11—Preparation of6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol

Step 1 Preparation of6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol

2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethan-1-one(0.25 g, 0.70 mmol) in DMF (Volume: 1 ml) was de-gassed under N₂ flowfor 10 minutes. The reaction mixture was charged with a preformedmixture of formic acid (49.9 mg, 0.70 mmol) and triethylamine (0.196 ml,1.40 mmol). This was then followed by catalystRuCl(p-Cymene)-[(R,R-pTs-DPEN)] (13.4 mg, 0.021 mmol), and reaction wasallowed to stir at room temperature under inert N₂ atmosphere overnight.The reaction was quenched with saturated NaHCO₃ solution and dilutedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by SFC (method S) to give6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-olas a beige foam (121 mg, 46%). ¹H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H),8.02 (d, J=2.4 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.24-6.99 (m, 4H),6.99-6.80 (m, 1H), 4.98 (d, J=4.4 Hz, 1H), 4.92-4.77 (m, 1H), 4.60 (dt,J=4.5, 8.4 Hz, 1H), 2.74-2.44 (m, 5H), 2.42-2.18 (m, 2H), 2.06-1.82 (m,2H), 1.65 (dt, J=4.9, 13.1 Hz, 2H). LC-MS: [M+H]⁺ 359.4 Rt=0.99 min.method R.

TABLE 3 The following compounds were prepared by the method describedabove. Cal- Retention culated Found time Structure IUPAC Name M + H M +H (min) Method

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5-((2- methylpyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 353.4 353.20.864 M

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5-((2- methylpyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethyl)phenol 355.44355.2 1.091 A

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5- phenoxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethanone 338.41 338.2 1.964 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- phenoxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethyl)phenol 340.42 304.2 1.822 A

1-(5-hydroxypyridin-2- yl)-2-((3aR,5s,6aS)-5- phenoxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethanone 339.40 339.2 6.337 N

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- phenoxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethyl)phenol 341.42 341.2 1.936 A

2-((3aR,5s,6aS)-5-((6- fluoropyridin-3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 358.38358.2 1.744 A

rac-6-(2-((3aR,5s,6aS)- 5-((6-fluoropyridin-3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 3-ol 360.39 360.21.487 A

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 357.39 357.22.284 A

rac-4-(2-((3aR,5s,6aS)- 5-((6-fluoropyridin-3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol 359.41 359.2 2.095 A

1-(5-hydroxypyridin-2- yl)-2-((3aR,5s,6aS)-5-(3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethanone 369.43 369.5 1.953 A

rac-6-(1-hydroxy-2- ((3aR,5s,6aS)-5-(3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)ethyl)pyridin- 3-ol 371.44 371.5 1.699A

2-((3aR,5s,6aS)-5-(2- fluorophenoxy)hexahydro- cyclopenta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 356.4 356.2 1.991 A

rac-4-(2-((3aR,5s,6aS)- 5-(2- fluorophenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 358.4 358.2 1.839A

2-((3aR,5s,6aS)-5-(2- fluorophenoxy)hexahydro- cyclopenta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 357.3 357.2 2.022 A

rac-6-(2-((3aR,5s,6aS)- 5-(2- fluorophenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 359.4 359.21.755 A

3-(((3aR,5s,6aS)-2-(2- (5-hydroxypyridin-2-yl)- 2-oxoethyl)octahydrocyclo- penta[c]pyrrol-5- yl)oxy)benzonitrile 364.4364.2 1.965 A

2-((3aR,5s,6aS)-5-(2,4- difluorophenoxy)hexahy- drocyclopenta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 375.39 375.4 2.084 A

rac-6-(2-((3aR,5r,6aS)- 5-(2,4- difluorophenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 377.16377.2 2.374 J

2-((3aR,5s,6aS)-5-(2,6- difluorophenoxy)hexahy- drocyclopenta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 374.4 374.2 3.024 K

rac-4-(2-((3aR,5s,6aS)- 5-(2,6- difluorophenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 376.41 376.22.756 A

2-((3aR,5s,6aS)-5-(2,6- difluorophenoxy)hexahy- drocyclopenta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 375.38 375.1 2.876 K

rac-6-(2-((3aR,5s,6aS)- 5-(2,6- difluorophenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 377.4377.2 2.672 K

2-((3aR,5s,6aS)-5-(2,4- difluorophenoxy)hexahy- drocyclopenta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 374.39 374.1 1.514 O

rac-4-(2-((3aR,5s,6aS)- 5-(2,4- difluorophenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 376.42 376.12.957 K

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5-((2- methoxypyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 369.43 369.21.856 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5-((2- methoxypyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethyl)phenol 371.44371.2 1.652 A

2-((3aR,5s,6aS)-5-(2- fluoro-6- methxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone387.42 387.1 2.973 J

rac-6-(2-((3aR,5s,6aS)- 5-(2-fluoro-6- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 389.43389.2 2.503 J

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyridin-4-yloxy)hexahydrocyclopen- ta[c]pyrrol-2(1H)- yl)ethanone 339.0 339.23.141 C

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- (pyridin-4-yloxy)hexahydrocyclopen- ta[c]pyrrol-2(1H)- yl)ethyl)phenol 341.42 341.23.532 L

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (isoquinolin-5-yloxy)hexahydrocyclopen- ta[c]pyrrol-2(1H)- yl)ethanone 389.46 389.21.462 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- (isoquinolin-5-yloxy)hexahydrocyclopen- ta[c]pyrrol-2(1H)- yl)ethyl)phenol 391.47 391.21.326 A

2-((3aR,5s,6aS)-5-((2- fluoropyridin-3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 358.38358.2 1.853 A

rac-6-(2-((3aR,5s,6aS)- 5-((2-fluoropyridin-3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 3-ol 369.39 360.21.386 A

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5-((2- fluoropyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 375.38 375.11.72 A

rac-2-fluoro-4-(2- ((3aR,5s,6aS)-5-((2- fluoropyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol377.4 377.2 1.67 A

2-((3aR,5s,6aS)-5-(2- fluoro-4-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone371.17 371.2 3.109 A

rac-6-(2-((3aR,5s,6aS)- 5-(2-fluoro-4-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 373.43373.2 2.628 J

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyrazin-2-yloxy)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 340.38 340.22.517 J

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- (pyrazin-2- yloxy)hexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethyl)phenol 342.40 342.3 6.803 C

2-((3aR,5s,6aS)-5-(2- fluoro-3-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone371.42 371.2 3.109 K

rac-6-(2-((3aR,5s,6aS)- 5-(2-fluoro-3-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 373.43373.5 2.616 J

2-((3aR,5s,6aS)-5-(2- fluoro-5- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone387.42 387.2 3.011 J

rac-6-(2-((3aR,5s,6aS)- 5-(2-fluoro-5- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 389.43389.2 2.535 J

2-((3aR,5s,6aS)-5-(2- fluoro-5- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 386.43386.2 2.6 J

rac-4-(2-((3aR,5s,6aS)- 5-(2-fluoro-5- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 388.44 388.32.752 J

2-((3aR,5r,6aS)-5-(2,3- difluorophenoxy)hexahy- drocyclopenta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 375.14 375.4 1.477 O

rac-6-(2-((3aR,5s,6aS)- 5-(2,3- difluorophenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 377.16377.2 2.585 A

2-((3aR,5s,6aS)-5-(2- fluoro-3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone387.42 387.2 2.54 J

rac-6-(2-((3aR,5s,6aS)- 5-(2-fluoro-3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 389.43389.2 2.493 A

2-((3aR,5s,6aS)-5-(2- fluoro-3-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 370.43 370.22.9 K

rac-4-(2-((3aR,5s,6aS)- 5-(2-fluoro-3-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 372.45 372.2 2.851A

2-((3aR,5s,6aS)-5-(2- fluoro-3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 386.43386.2 2.795 A

rac-4-(2-((3aR,5s,6aS)- 5-(2-fluoro-3- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 388.44 388.52.717 A

2-((3aR,5s,6aS)-5-((2- fluoro-6-methylpyridin- 3- yl)oxy)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 372.41372.2 2.63 A

rac-6-(2-((3aR,5s,6aS)- 5-((2-fluoro-6- methylpyridin-3-yl)oxy)hexahydrocyclo- penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin-3-ol 374.42 374.2 2.36 A

2-((3aR,5s,6aS)-5-(2- fluoro-6- methoxyphenoxy)hexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 386.43386.2 2.807 K

rac-4-(2-((3aR,5s,6aS)- 5-(2-fluoro-6- methoxyphenoxyhexahy-drocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 388.44 388.32.727 A

2-((3aR,5s,6aS)-5-(2- chlorophenoxy)hexa- hydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 373.85 373.1 2.891 K

rac-6-(2-((3aR,5s,6aS)- 5-(2-chloro- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin-3- ol 375.86375.1 2.613 A

1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyrimidin-5-yloxy)hexahydrocyclopen- ta[c]pyrrol-2(1H)- yl)ethanone 340.16 340.2 2.262 A

rac-4-(1-hydroxy-2- ((3aR,5s,6aS)-5- (pyrimidin-5- yloxy)hexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethyl)phenol 342.40 342.3 2.05 P

2-((3aR,5s,6aS)-5-(2- fluoro-4-methyl- phenoxy)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 370.43 370.22.913 A

rac-4-(2-((3aR,5s,6aS)- 5-(2-fluoro-4- methylphenoxy)hexa-hydrocyclopenta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 372.45 372.22.852 Q

6-((S)-2-((3aR,5R,6aS)- 5-((2-fluoropyridin-3-yl) oxy)hexahydrocyclopen-ta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 3-ol 360.16 360.2 1.276 A

The minor isomer 2A can also be used to create compounds with theopposite relative configuration as shown in the following examples

Example 12—Preparation of (3aR,5r,6aS)-benzyl5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Step 1 Preparation of (3aR,5s,6aS)-benzyl5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,5s,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.4 g, 5.364mmol) in dichloromethane (30 mL) was added triethylamine (2.24 mL,16.091 mmol) at room temperature. The reaction mixture was cooled to 0°C., and methanesulfonyl chloride (1.1 mL, 10.727 mmol) was slowly added.The resultant mixture was allowed to warm to room temperature andstirred for 3 h. The solution was diluted with ice-water (25 mL) andextracted with dichloromethane (100 mL×3). The combined extracts werewashed with sodium bicarbonate solution (100 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford the title compound(3aR,5s,6aS)-benzyl5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.8 g, 98.9%) as a brownish liquid. Calculated M+H: 340.4; Found M+H:340.1.

Step 2 Preparation of (3aR,5r,6aS)-benzyl5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,5s,6aS)-benzyl5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.5 g, 4.424 mmol) in acetonitrile (20 mL) were added 4-fluorophenol(1.0 g, 8.849 mmol) and cesium carbonate (2.87 g, 8.849 mmol) at roomtemperature. The reaction mixture was heated at 80° C. for 18 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycombiflash purifier using 10% ethyl acetate in hexane to afford thetitle compound (3aR,5r,6aS)-benzyl5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.7g, 44.58% yield) as a colorless liquid. Calculated M+H: 356.4; FoundM+H: 356.3.

TABLE 4 The following compounds were prepared by the method of Example12. Retention Calculated Found time Structure IUPAC Name M + H M + H(min) Method

2-((3aR,5r,6aS)-5-(4- fluorophenoxy)hexahy- drocyclopenta[c]pyr-rol-2(1H)-yl)-1-(4- hydroxyphenyl)ethan- one 356.4 356.2 2.061 A

rac-2-fluoro-4-(2- ((3aR,5r,6aS)-5-(4- fluorophenoxy)hexahy-drocyclopenta[c]pyr- rol-2(1H)-yl)-1- hydroxyethyl)phenol 358.4 358.21.886 A

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5r,6aS)-5-(4-fluorophenoxy)hexahy- drocyclopenta[c]pyr- rol-2(1H)- yl)ethanone 374.39374.5 2.055 A

rac-2-fluoro-4-(2- ((3aR,5r,6aS)-5-(4- fluorophenoxy)hexahy-drocyclopenta[c]pyr- rol-2(1H)-yl)-1- hydroxyethyl)phenol 376.41 376.38.537 B

1-(4- hydroxyphenyl)-2- ((3aR,5s,6aS)-5- (pyridin-3-yloxy)hexahydrocyclo- penta[c]pyrrol- 2(1H)-yl)ethanone 339.40 339.21.063 A

rac-4-(1-hydroxy-2- ((3aR,5r,6aS)-5- (pyridin-3- yloxy)hexahydrocyclo-penta[c]pyrrol- 2(1H)- yl)ethyl)phenol 341.42 341.2 7.231 C

2-((3aR,5r,6aS)-5- (3,4- difluorophenoxy)hex- ahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- (4- hydroxyphenyl)ethan- one 374.39 374.4 2.105 A

rac-4-(2- ((3aR,5r,6aS)-5-(3,4- difluorophenoxy)hex- ahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)phenol 376.4 376.2 1.348 D

rac-6-(2- ((3aR,5r,6aS)-5-(3,4- difluorophenoxy)hex- ahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol 377.39 377.4 1.863 A

2-((3aR,5r,6aS)-5- (3,5- difluorophenoxy)hex- ahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- (5-hydroxypyridin-2- yl)ethanone 375.38 375.4 1.988A

rac-6-(2- ((3aR,5r,6aS)-5-(3,5- difluorophenoxy)hex- ahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol 377.4 377.4 1.845 A

Example 13—Preparation ofrac-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanol

Step 1 Preparation of tert-butyl 4-bromo-1H-pyrazole-1-carboxylate

Boc anhydride (2.34 mL, 10.2 mmol) was added to a solution of4-bromo-1H-pyrazole (1 g, 6.8 mmol), triethylamine (3.3 mL, 23.8 mmol)and 4-dimethylaminopyridine (0.166 g, 1.36 mmol) in acetonitrile (20 mL)at 0° C., and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted with ethylacetate (100 mL×3). The combined organic extract was washed with water(100 mL), brine (100 mL), dried over anhydrous sodium sulfate andevaporated. The crude material was purified by combiflash purifier using10% ethyl acetate in hexane to afford the title compound tert-butyl4-bromo-1H-pyrazole-1-carboxylate (1.65 g, 98% yield) as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H). 7.66 (s, 1H), 1.65 (s,9H).

Step 2 Preparation of tert-butyl4-(1-ethoxyvinyl)-1H-pyrazole-1-carboxylate

Nitrogen was purged into a solution of tert-butyl4-bromo-1H-pyrazole-1-carboxylate (0.75 g, 3.03 mmol) andtributyl(1-ethoxyvinyl)stannane (1.13 mL, 3.34 mmol) in toluene (10 mL)for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.175 g, 0.152mmol) was added and the reaction mixture was heated at 110° C. for 12 h.The reaction mixture was filtered through celite and the filtrate wasevaporated to afford the title compound tert-butyl4-(1-ethoxyvinyl)-1H-pyrazole-1-carboxylate (0.7 g, crude) as a blackliquid. The crude material was as such taken for next step withoutfurther purification.

Step 3 Preparation of tert-butyl4-(2-bromoacetyl)-1H-pyrazole-1-carboxylate

N-Bromosuccinimide (0.52 g, 2.94 mmol) was added to a solution oftert-butyl 4-(1-ethoxyvinyl)-1H-pyrazole-1-carboxylate (0.7 g, 2.94mmol) in tetrahydrofuran (15 mL) and water (5 mL) at 0° C., and thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water and extracted with ethyl acetate (100mL×2). The combined organic extract was washed with brine (50 mL), driedover anhydrous sodium sulfate and evaporated. The crude material waspurified by combiflash purifier using 20% ethyl acetate in hexane toafford the title compound tert-butyl4-(2-bromoacetyl)-1H-pyrazole-1-carboxylate as a colorless liquid (0.31g, 35% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.14 (s, 1H),4.42 (s, 2H), 1.68 (s, 9H).

Step 4 Preparation of tert-butyl4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-1H-pyrazole-1-carboxylate

To a solution of(3aR,5s,6aS)-5-(4-fluorophenoxy)octahydrocyclopenta[c]pyrrole (0.24 g,1.08 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.45g, 3.25 mmol) followed by tert-butyl4-(2-bromoacetyl)-1H-pyrazole-1-carboxylate (0.31 g, 1.08 mmol). Theresulting suspension was stirred at room temperature for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Thecrude was purified by combiflash purifier using 3% methanol indichloromethane to afford the title compound tert-butyl4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-1H-pyrazole-1-carboxylate(0.2 g, 43% yield) as a gummy material. Calculated (M+H)-boc: 330.38;Found (M+H)-boc: 330.4.

Step 5 Preparation of2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanonehydrochloride

Hydrochloric acid in dioxane (1.5 mL) was added to a solution oftert-butyl4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-1H-pyrazole-1-carboxylate(0.15 g, 0.35 mmol) in dichloromethane (10 mL) at 0° C., and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was evaporated to dryness. The crude material was trituratedwith diethyl ether in pentane (50 mL, 50%) and dried to afford the titlecompound2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanonehydrochloride (0.09 g, 70% yield) as a white solid. Calculated M+H:330.38; Found M+H: 330.4.

Step 6 Preparation ofrac-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanol

To a solution of2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanonehydrochloride (0.09 g, 0.246 mmol) in methanol (10 mL) was added sodiumborohydride (0.09 g, 2.46 mmol)) at 0° C. The reaction mixture wasstirred at room temperature for 2 h and concentrated. The residue wasdiluted with water (50 mL) and extracted with dichloromethane (100mL×2). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was washed with ether inpentane (50 mL, 50%) to afford the title compound2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanol(0.065 g, 80.0% yield) as a white solid. Calculated M+H: 332.39; FoundM+H: 332.4.

Example 14—Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethanone

Step 1 Preparation of 1-benzyl-4-bromo-1H-pyrazole

Sodium hydride (0.2 g, 60%, 5.1 mmol) was added to a solution of4-bromo-1H-pyrazole (0.5 g, 3.4 mmol) in N,N-dimethylformamide (10 mL)at 0° C., and stirred at mom temperature for 30 minutes. The reactionmixture was cooled to 0° C. added benzyl bromide (0.485 mL, 4.08 mmol)and stirred at room temperature for 2 h. The reaction mixture wasdiluted with ice-water (30 mL) and extracted with ethyl acetate (50mL×2). The combined organic extract was washed with water (30 mL), brine(30 mL), dried over anhydrous sodium sulfate and evaporated. The crudematerial was purified by combiflash purifier using 7% ethyl acetate inhexane to afford the title compound 1-benzyl-4-bromo-1H-pyrazole (0.7 g,87% yield) as a colorless liquid. Calculated M+H: 236.99; Found M+H:236.9.

Step 2 Preparation of 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole

Nitrogen was purged into a solution of 1-benzyl-4-bromo-1H-pyrazole(0.55 g, 2.32 mmol) and tributyl(1-ethoxyvinyl)stannane (0.862 mL, 2.55mmol) in toluene (15 mL) for 15 minutes. Thentetrakis(triphenylphosphine)palladium(0) (0.134 g, 0.116 mmol) was addedand the reaction mixture was heated at 110° C. for 12 h. The reactionmixture was filtered through celite and the filtrate was evaporated toafford the title compound 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole (0.52g, crude) as a black liquid. The crude material was as such taken fornext step without further purification.

Step 3 Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethanone

N-Bromosuccinimide (0.487 g, 2.74 mmol) was added to a solution of1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole (0.52 g, 2.28 mmol) intetrahydrofuran (15 mL) and water (5 mL) at 0° C., and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with water (30 mL) and extracted with ethyl acetate (50mL×2). The combined organic extract was washed with brine (30 mL), driedover anhydrous sodium sulfate and evaporated. The crude material waspurified by combiflash purifier using 20% ethyl acetate in hexane toafford the title compound 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethanone(0.23 g, 36% yield) as a colorless liquid. Calculated M+H: 279.01; FoundM+H: 279.0.

TABLE 5 The following compounds were prepared by the method of Example14. Retention Calculated Found time Structure IUPAC Name M + H M + H(min) Method

1-(1-benzyl-1H-pyrazol-4- yl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydro- cyclopenta[c]pyrrol- 2(1H)-yl)ethanone 420.49420.5 2.248 A

rac-1-(1-benzyl-1H- pyraozl-4-yl)-2- ((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydro- cyclopenta[c]pyrrol- 2(1H)-yl)ethanol 422.51422.2 2.104 A

Example 15—Preparation ofrac-4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-methoxyethyl)phenol

Step 1 Preparation of 1-(4-(benzyloxy)phenyl)-2-bromoethanone

To a solution of 2-bromo-1-(4-hydroxyphenyl)ethanone (2 g, 9.3 mmol) intetrahydrofuran (70 mL) was added silver carbonate (5.128 g, 18.6 mmol)and the reaction mixture was cooled to 0° C. Benzyl bromide (1.32 mL,11.16 mmol) was added drop wise and the reaction mixture was stirred atroom temperature for 16 h. The reaction mixture was filtered throughcelite, the filtrate was diluted with ethyl acetate (200 mL) and washedwith water (60 mL×2). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified by columnchromatography using 6% ethyl acetate in hexane to afford title1-(4-(benzyloxy)phenyl)-2-bromoethanone (1.22 g, 43% yield) as a whitesolid. Calculated M+H: 306.17; Found M+H: 306.

Step 2 Preparation of1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of(3aR,5s,6aS)-5-(4-fluorophenoxy)octahydrocyclopenta[c]pyrrole (0.7 g,3.165 mmol) in acetonitrile (25 mL) was added potassium carbonate (1.312g, 9.495 mmol) followed by 1-(4-(benzyloxy)phenyl)-2-bromoethanone(0.866 g, 2.849 mmol). The resulting suspension was stirred at roomtemperature for 2 h. The reaction mixture was filtered and the filtratewas concentrated. The crude was purified by column chromatography using15% ethyl acetate in hexane to afford the title compound1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(1.06 g, 75% yield) as a white solid. Calculated M+H: 446.53; Found M+H:446.2

Step 3 Preparation ofrac-1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanol

To a solution of1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(1.06 g, 2.38 mmol) in ethanol (50 mL) was added sodium borohydride(1.35 g, 35.713 mmol). The reaction mixture was stirred at roomtemperature for 4 h and concentrated. The residue was diluted with water(50 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified column chromatography using 22%ethyl acetate in hexane to afford the title compound1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanol(0.63 g, 59% yield) as a white solid. Calculated M+H: 448.54; Found M+H:448.2

Step 4 Preparation ofrac-(3aR,5s,6aS)-2-(2-(4-(benzyloxy)phenyl)-2-methoxyethyl)-5-(4-fluorophenoxy)octahydrocyclopenta[c]pyrrole

To a solution of1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanol(0.23 g, 0.514 mmol) in N,N-dimethyl formamide (6 mL) was addedpotassium carbonate (0.213 g, 1.543 mmol). The reaction mixture wascooled to 0° C., and dimethyl sulfate (0.146 mL, 1.543 mmol) was addeddrop wise. The resulting suspension was stirred at room temperature for1.5 h. The reaction mixture was diluted with ethyl acetate (200 mL)washed with water (40 mL×2). The organic layer was dried over anhydroussodium sulfate filtered and concentrated to afford the title compound(3aR,5s,6aS)-2-(2-(4-(benzyloxy)phenyl)-2-methoxyethyl)-5-(4-fluorophenoxy)octahydrocyclopenta[c]pyrrole(0.24 g, crude) as a white solid. Calculated M+H: 462.57; Found M+H:462.2.

Step 5 Preparation ofrac-4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-methoxyethyl)phenol

To a solution of(3aR,5s,6aS)-2-(2-(4-(benzyloxy)phenyl)-2-methoxyethyl)-5-(4-fluorophenoxy)octahydrocyclopenta[c]pyrrole(0.24 g, 0.52 mmol) in methanol (15 mL), Pd/C (0.04 g, 10% dry) andtriethylsilane (1.65 mL, 10.4 mmol) were added. The resulting suspensionwas stirred at room temperature for 18 h. The reaction mixture wasfiltered through celite and the filtrate was concentrated. The crude waspurified by preparative HPLC (analytical conditions: column: Zorbax XDBC18 (150 mm×4.6 mm×3.5 μm), mobile phase (A): 5 mM ammonium acetate inwater, mobile phase (B): acetonitrile, flow rate: 1.0 mL/min T/% B:0/20, 10/70, 25/70, 27/20, 30/20) to afford the title compound4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-methoxyethyl)phenol(0.015 g, 7%) as a brown solid. Calculated M+H: 372.45; Found M+H: 372.5

Example 16—Preparation of (3aR,5s,6aS)-benzyl5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,5r,6aS)-benzyl5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.5 g, 1.915mmol) in tetrahydrofuran (5 mL) cooled at 0° C. were added4-nitrobenzoic acid (0.32 g, 1.915 mmol), triphenylphosphine (0.6 g,2.29 mmol) and diethyl azo dicarboxylate (0.45 mL, 2.87 mmol). Thereaction mixture was heated at 60° C. in microwave for 3 h andconcentrated. Then the crude material was purified by combiflashpurifier using 20% ethyl acetate in hexane to afford the title compound(3aR,5s,6aS)-benzyl5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.65 g, 83.33% yield) as a white solid. Calculated M+H: 411.42; FoundM+H: 411.2.

Example 17—Preparation ofrac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

Step 1 Preparation of (3aR,5s,6aS)-benzyl5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a mixture of (3aR,5r,6aS)-benzyl5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(2.7 g, 7.954 mmol) and potassium carbonate (2.74 g, 19.88 mmol) inacetonitrile (50 mL) was added benzenethiol (1.22 mL, 11.93 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature andstirred for 18 h. The progress of the reaction was monitored by TLC. Thereaction mixture was filtered through celite pad, the bed was washedwith ethyl acetate and the combined filtrate was concentrated to affordthe crude product which was purified by silica gel column chromatographyusing 8% ethyl acetate in hexane to obtain the title compound(3aR,5s,6aS)-benzyl5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.6 g,56% yield) as a colorless semi solid. Calculated (M+H): 354.48; Found(M+H): 354.4

Step 2 Preparation of(3aR,5s,6aS)-5-(phenylthio)octahydrocyclopenta[c]pyrrole

To a solution of (3aR,5s,6aS)-benzyl5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g,2.82 mmol) in tetrahydrofuran (10 mL) was added lithiumtriethylborohydride, (1M solution in tetrahydrofuran, 1.49 g, 14.14mmol) under nitrogen atmosphere at 0° C. The reaction mixture wasallowed to warm to room temperature and stirred for 3 h. The mixture wasquenched with saturated solution of ammonium chloride (10 ml), extractedwith ethyl acetate (100 mL×3), dried over sodium sulfate, filtered andconcentrated to afford crude product(3aR,5s,6aS)-5-(phenylthio)octahydrocyclopenta[c]pyrrole (1.2 g, crude)which was taken as such to the next step without further purification.Calculated (M+H): 220.11; Found (M+H): 220.3.

Step 3 Preparation of1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of(3aR,5s,6aS)-5-(phenylthio)octahydrocyclopenta[c]pyrrole (0.3 g, 1.36mmol) in acetonitrile (10 mL) was added potassium carbonate (0.47 g,3.42 mmol) at 0° C. followed by the addition of2-bromo-1-(4-hydroxyphenyl) ethanone (0.29 g, 1.36 mmol). The resultingsuspension was gradually allowed to warm to room temperature and stirredfor 3 h. The reaction mixture was filtered and washed with 10% methanolin dichloromethane, the combined filtrate was concentrated under vacuumto afford crude product, which was purified by silica gel columnchromatography using 10% methanol in dichloromethane and again purifiedby preparative HPLC (Column: Zorbax XDB C18 (150 mm×4.6 mm×3.5 μm).Mobile phase (A): 0.01% Formic acid in water, Mobile phase (B):acetonitrile, Flow rate: 1.0 mL/min, T/% B:0/20.10/70,25/70,27/20,30/20) to obtain the title compound1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.14 g, 29% yield) as a colorless solid. Calculated (M+H): 354.48;Found (M+H): 354.4.

Step 4 Preparation ofrac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

To a solution of1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.1 g, 0.28 mmol) in ethanol (10 mL) was added sodium borohydride (0.21g, 5.65 mmol) at room temperature and stirred for 3 h. The reactionmixture was diluted with water (25 mL) and concentrated under vacuum.The aqueous residue was extracted with dichloromethane (50 mL×3), thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford crude product which was purifiedby silica gel column chromatography using 4% methanol in dichloromethaneto afford the title compound4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol(0.045 g, 45% yield) as a white solid. Calculated (M+H): 356.49; Found(M+1): 356.3.

TABLE 6 The following compounds were prepared by the method describedabove. Retention IUPAC Calculated Found time Structure Name (M + H) (M +H) (min) Method

1-(4- hydroxyphe- nyl)-2- ((3aR,5s,6aS)- 5-((4- methoxyphenyl)yl)thio)hexahy- drocyclopen- ta[c]pyrrol- 2(1H)- yl)ethanone 384.16384.2 1.602 D

2- ((3aR,5s,6aS)- 5-((4- fluorophenyl) thio)hexahydro- cyclopenta[c]pyrrol- 2(1H)-yl)-1- (4-hydroxy- phenyl) ethanone 372.14 372.1 2.096 E

rac-4-(2- ((3aR,5s,6aS)- 5-((4- fluorophenyl) thio)hexahydro-cyclopenta[c] pyrrol- 2(1H)-yl)-1- hydroxyethyl) phenol 374.15 374.11.975 A

rac-4-(1- hydroxy-2- ((3aR,5s,6aS)- 5-((4-meth- oxyphenyl) thio)hexahy-drocyclopen- ta[c]pyrrol- 2(1H)-yl) ethyl)phenol 386.17 386.2 2.086 A

rac-6-(2- ((3aR,5s,6aS)- 5-((2- fluorophenyl) thio)hexahydro-cyclopenta[3] pyrrol- 2(1H)-yl)-1- hydroxyethyl) pyridin-3-ol 375.15375.1 1.302 D

Example 18—Preparation ofrac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

Step 1 Preparation of (3aR,5s,6aS)-benzyl5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a mixture of (3aR,5s,6aS)-benzyl5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.7 g,1.98 mmol), trifluoro acetic acid (5 mL) and dichloromethane (5 mL) wasadded hydrogen peroxide (1.12 mL, 9.95 mmol, aqueous 35%) at 0° C. Thereaction mixture was allowed to warm to room temperature and stirred for3 h. The progress of the reaction was monitored by TLC. The reactionmixture was cooled to 0° C., and neutralized with saturated sodiumbicarbonate solution to pH=7. The mixture was extracted withdichloromethane (150 mL×3), the combined organic layer was washed withwater (100 mL), brine solution (100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the crudeproduct which was purified by silica gel column chromatography using 35%ethyl acetate in hexane to obtain title compound (3aR,5s,6aS)-benzyl5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.63g, 83% yield) as a colorless semi solid. Calculated (M+H): 386.53; Found(M+H): 386.1.

Step 2 Preparation of(3aR,5s,6aS)-5-(phenylsulfonyl)octahydrocyclopenta[c]pyrrole

To a stirred solution of (3aR,5s,6aS)-benzyl5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.38g, 0.98 mmol) in ethanol (10 mL), was added 10% Pd/C (0.1 g) undernitrogen atmosphere. The reaction was subjected to hydrogenation inballoon and stirred for 2 h. After completion of reaction, the mixturewas filtered through celite and the bed was washed with methanol. Thecombined filtrate was concentrated under vacuum to obtain the titlecompound (3aR,5s,6aS)-5-(phenylsulfonyl)octahydrocyclopenta[c]pyrrole(0.22 g, crude) as a colorless gum. Calculated (M+H): 252.1; Found(M+H): 252.2.

Step 3 Preparation of1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a solution of(3aR,5s,6aS)-5-(phenylsulfonyl)octahydrocyclopenta[c]pyrrole (0.21 g,0.83 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.28g, 2.08 mmol) at 0° C. followed by the addition of2-bromo-1-(4-hydroxyphenyl) ethanone (0.18 g, 0.835 mmol). The resultingsuspension was gradually allowed to warm to room temperature and stirredfor 2 h. The reaction mixture was filtered and washed with 10% methanolin dichloromethane. The combined filtrate was concentrated under vacuumto afford crude product, which was purified by silica gel columnchromatography using 10% methanol in dichloromethane and again purifiedby preparative HPLC: (Column: Zorbax XDB C18 (150 mm×4.6 mm×3.5 μm),Mobile phase (A): 0.01% Formic acid, Mobile phase (B): Acetonitrile,Flow rate: 1.0 mL/min. T/% B: 0/20.10/70, 25/70.27/20,30/20) to obtaintitle compound1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.14 g, 43% yield) as a colorless solid. Calculated (M+H): 386.13;Found (M+H): 386.1.

Step 4 Preparation ofrac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

To a solution of1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.15 g, 0.39 mmol) in ethanol (10 mL) was added sodium borohydride(0.29 g, 7.78 mmol)) at room temperature and stirred for 4 h. Thereaction mixture was diluted with water (25 mL) and concentrated undervacuum. The aqueous residue was extracted with dichloromethane (50mL×3), the combined organic layer was dried over anhydrous sodiumsulfate, filtered, concentrated under vacuum to afford crude productwhich was purified by silica gel column chromatography using 7% methanolin dichloromethane to afford the title compound4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol(0.042 g, 28% yield) as a white solid. Calculated (M+H): 388.15; Found(M+H): 388.4.

TABLE 7 The following compounds were prepared by the method describedabove. Retention Calculated Found time Structure IUPAC Name (M + H) (M +H) (min) Method

1-(3-fluoro-4- hydroxyphenyl)- 2-((3aR,5s,6aS)- 5- (phenylsulfonyl)hex-ahydrocyclopen- ta[c]pyrrol- 2(1H)- yl)ethanone 404.13 404.1 1.795 A

rac-2-fluoro-4- (1-hydroxy-2- ((3aR,5s,6aS)-5- (phenylsulfonyl)hex-ahydrocyclopen- tac]pyrrol- 2(1H)- yl)ethyl)phenol 406.14 406.1 4.11 C

Example 19—Cell Assay

Cell Culture and plating: HEK293 cells expressing NR1/NR2B (Chantest,Cleveland, Ohio) were grown to 70-80% confluency as an adherentmonolayer in standard tissue culture flasks at 37° C., 5% CO₂ persupplier's instructions. NR2B expression was induced by incubation with0.3-0.4 μg/ml tetracycline in the presence of 4 mM ARL-15896 for 18-24hours under the same growth conditions, then transferred to 30° C. foranother 3-5 hours.

After induction, cell culture medium was removed and cells were rinsedonce with Ca²⁺ and Mg²⁺-free Dulbecco's phosphate buffered saline. Cellswere then removed from the flask using TrypLE™ Express (LifeTechnologies) according to the manufacturer's instructions and collectedto 50 ml centrifuge tubes. Following two washes in Ca²⁺/Mg²⁺-free HBSSwith 20 mM HEPES (HHnoCa), cells were counted and viability assessedusing trypan blue. To load cells with Ca²⁺-sensitive dye, they wereresuspended in fluo-8 plus Component B (AAT Bioquest Products) dilutedin HHnoCa and incubated 15 minutes at 37° C., followed by 30 minutes atroom temp (in dark). Cells were then washed and resuspended in HHnoCa toremove extracellular dye and plated in 384-well plates (Falcon,uncoated) at 20.000-30,000 cells/well in a final volume of 25 μl/well.

FDSS Assay: To each well of the plate, 10 μL test compound, control(MK801) or HHnoCa buffer was added at different concentrations to yieldfinal concentrations of 0.001, 0.003, 0.010, 0.030, 0.100, 0.300, 1.000,3.000, 10.000, or 30.000 uM final concentration of DMSO of 0.1%.Following 10 minutes pre-incubation in the dark, plates are loaded ontothe Hamamatsu FDSS 6000. After collecting baseline fluorescence images.3 μM glutamate, 3 μM glycine, and 1 mM Ca²⁺ in HHnoCa buffer is added toeach well, and Ca²⁺ is recorded for 3 minutes. Data were processed bycomputing ratio of fluorescence at the end of data collection tobaseline fluorescence to assess degree of Ca²⁺ influx inhibitionrelative to that observed in MK801.

Table 8 below provides activity of each compound according to the legendthat “++++” indicates inhibition at a concentration <100 nM; “+++”indicates inhibition at a concentration between 100 nM and 1 μM of thedisclosed compound: “++” indicates inhibition at a concentration of from1 μM to 10 μM; and “+” indicates inhibition at a concentration >10 μM.

TABLE 8 NR2B NAM Assay NR2B NAM Activity Structure IC₅₀ (M) Category

4.70E-08 ++++

1.30E-08 ++++

6.16E-08 ++++

1.40E-08 ++++

1.26E-06 ++

6.99E-07 +++

1.78E-08 ++++

1.00E-05 +

5.83E-08 ++++

8.15E-08 ++++

2.53E-07 +++

4.93E-07 +++

1.00E-05 +

1.00E-05 +

5.34E-08 ++++

9.46E-08 ++++

1.00E-05 +

8.45E-08 ++++

1.00E-05 +

1.80E-08 ++++

3.67E-07 +++

4.34E-07 +++

1.00E-05 +

4.64E-08 ++++

1.02E-07 +++

1.00E-05 +

6.82E-08 ++++

4.74E-08 ++++

2.67E-07 +++

4.89E-06 ++

5.21E-08 ++++

1.00E-05 +

1.40E-07 +++

1.00E-05 +

1.33E-06 ++

6.58E-08 ++++

4.15E-08 ++++

5.16E-08 ++++

7.07E-08 ++++

3.02E-08 ++++

1.00E-05 +

1.98E-06 ++

2.92E-06 ++

5.73E-08 ++++

2.50E-07 +++

8.39E-08 ++++

5.32E-08 ++++

3.05E-08 ++++

2.37E-06 ++

9.00E-08 ++++

1.12E-07 +++

7.10E-06 ++

1.78E-08 ++++

2.78E-06 ++

4.47E-06 ++

1.34E-07 +++

1.88E-07 +++

1.00E-05 +

3.29E-06 ++

5.22E-06 ++

8.00E-06 ++

1.00E-05 +

4.09E-07 +++

1.91E-07 +++

4.40E-07 +++

3.76E-08 ++++

1.00E-05 +

6.86E-08 ++++

6.20E-09 ++++

1.07E-08 ++++

5.96E-09 ++++

1.00E-05 +

1.00E-05 +

1.00E-05 +

2.09E-08 ++++

8.07E-08 ++++

1.00E-05 +

6.24E-06 ++

1.00E-05 +

4.44E-09 ++++

1.68E-08 ++++

5.72E-09 ++++

2.17E-08 ++++

5.52E-08 ++++

1.00E-05 +

7.41E-08 ++++

2.19E-07 +++

1.12E-07 +++

1.15E-06 ++

1.08E-06 ++

4.11E-08 ++++

2.25E-07 +++

2.93E-08 ++++

9.60E-09 ++++

8.62E-09 ++++

1.39E-07 +++

1.49E-07 +++

4.41E-09 ++++

4.35E-07 +++

1.00E-05 +

1.00E-05 +

1.63E-07 +++

5.47E-07 +++

6.31E-07 +++

5.69E-07 +++

3.08E-07 +++

6.81E-09 ++++

1.44E-08 ++++

3.78E-06 ++

2.34E-08 ++++

2.43E-07 +++

1.77E-07 +++

5.08E-08 ++++

1.17E-07 +++

7.26E-08 ++++

7.77E-08 ++++

1.00E-05 +

4.66E-07 +++

2.49E-07 +++

2.63E-08 ++++

1.66E-06 ++

1.04E-06 ++

8.78E-09 ++++

2.10E-07 +++

6.02E-08 ++++

3.80E-08 ++++

2.67E-08 ++++

9.36E-09 ++++

3.50E-06 ++

4.37E-06 ++

1.00E-05 +

1.00E-05 +

2.30E-07 +++

7.40E-08 ++++

1.92E-08 ++++

1.13E-07 +++

2.06E-08 ++++

5.25E-09 ++++

5.24E-09 ++++

8.30E-09 ++++

8.50E-09 ++++

2.00E-08 ++++

Example 20: PGP Efflux Assay

PgP is a protein present at the blood brain barrier and its substratesare subjected to efflux from the barrier, thereby limiting theirdistribution or partitioning into the CNS.

MDCK cells transfected with MDR1 (MDCK-MDR1) were seeded onto Costarpermeable support plates at a density of approximately 260,000 cell/cm²,and monolayers were ready for experimental use four days later.Compounds dissolved at 10 mM in 100% DMSO were diluted for experimentsand prepared in transport buffer (Hank's Balanced Salt Solution, 0.02%bovine serum albumin, 10 mM HEPES, pH 7.4). Compounds were tested at 10μM concentration and independently measured in two directions (apical tobasal and basal to apical) in triplicate. Prior to initiation of theexperiment, cells were washed three times in transport buffer. Monolayerefflux studies were conducted at 37° C. for 120 minutes. Markers formembrane integrity (bestatin) and efflux (quinidine) were included ineach experiment. Experimental samples plus internal standard (glyburide)were centrifuged for 10 minutes at 4000 rpm at 4° C. The samples werethen subject to analysis by mass spectroscopy using a RapidFireHigh-throughput MS System (Agilent RapidFire coupled to Sciex ABI4000mass spectrometer). The apparent permeability (P_(app)) was calculatedwith the equation P_(app)=V_(p)/AC₀×(C_(r)/t), where A is membranesurface area, C₀ is donor drug concentration at t=0, and C_(r) is theconcentration of the receiver compartment at time (t) 120 minutes. Ifthe ratio of Papp in the basal to apical to the Papp apical to basaldirection exceeds two in the assay (e.g. P_(app B>A)/P_(appA>B)>2), themolecule is considered to be a substrate of MDR1 (P-gP).

Certain compounds of the present disclosure have little PGP effluxliability and are readily partitioned across the blood brain barrier.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A method of modulating NR2B receptors in a subject comprisingadministering to the subject in need thereof an effective amount of acompound of formula I:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof, wherein: L₁ is straight or branched C₁-C₅ alkylene substitutedwith OH; R₁ is cycloalkyl, aryl, or heteroaryl, any of which optionallysubstituted with one or more substituents selected from the groupconsisting of OH, CN, halogen, —C₁-C₆alkylaryl, —O—C₁-C₆alkylaryl,O—R₁₀, OPO₃ ⁻²M₂, OP(O)(OH)₂, SH, S—R₁₀, C₁-C₅ alkyl, branched alkyl,NH₂, NHR₁₀, NHS(O)₂R₁₀, N(R₁₀)(R₁₀′), and NHCOR₁₀ where M is amonovalent metal cation; each R₁₀ and R₁₀′ is independently selectedfrom the group consisting of H; C₁-C₆ alkyl optionally substituted withone or more substituents selected from the group consisting of OH,O—C₁-C₅ alkyl, OPO₃ ⁻²M₂, OP(O)(OH)₂, OC(O)-alkyl, and OC(O)O-alkylwhere M is a monovalent metal cation; and cycloalkyl optionallysubstituted with one or more substituents selected from the groupconsisting of OH and O—C₁-C₅ alkyl provided that no more than one oxygenis attached to any carbon; or R₁₀ and R₁₀′, together with the nitrogento which they are attached, may form a heterocycle selected from thegroup consisting of oxetanyl, azetadinyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl; X is selected from O, S, —S(O)—, and —S(O)₂—; Y and Y′ areindependently H, halogen, or C₁-C₅ alkyl; L₂ is a bond, —(CH₂)_(n)— or—(CHR₁₁)_(n)—; each R₁₁ is independently selected from the groupconsisting of H, —C₁-C₅ alkylenyl-, —CO—C₁-C₅alkylenyl-, and-alkylenyl-CO-alkylenyl-; R₂ is phenyl, naphthyl, heteroaryl or bicyclicheteroaryl, each of which is optionally substituted with one or moresubstituents selected from the group consisting of halogen, OH,C₁-C₆alkyl, OR₁₀, CN, NH₂, NHR₁₀, N(R₁₀)(R₁₀′), -nitro, SH, SR₁₀, SOR₁₀,SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R₁₀′), CONH₂, CONR₁₀, and CON(R₁₀)(R₁₀′);and n is 1, 2, or 3; wherein cycloalkyl is a monocyclic saturated carbonring containing 3-18 carbon atoms; and wherein heteroaryl is amonocyclic, bicyclic or polycyclic aromatic radical of 5 to 10 ringatoms and containing one or more ring heteroatoms selected from N, O, orS, the remaining ring atoms being C, and when containing two fusedrings, the aryl groups may have an unsaturated or partially saturatedring fused with a fully saturated ring.
 2. The method of claim 1,wherein L₂ is a bond and R₂ is phenyl optionally substituted with one ormore halogen, OH, OR₁₀, CN, NH₂, NHR₁₀, N(R₁₀)(R₁₀′), SH, SR₁₀, SOR₁₀,SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R₁₀′), CONH₂, CONR₁₀, CON(R₁₀)(R₁₀′).
 3. Themethod of claim 2, wherein X is O.
 4. The method of claim 2, wherein R₁is aryl or heteroaryl each of which is substituted with one or moresubstituents selected from the group consisting of OH, halogen, OR₁₀,SH, SR₁₀, NH₂, NHR₁₀ and NHCOR₁₀.
 5. The method of claim 2, wherein Yand Y′ are hydrogen.
 6. The method of claim 1, wherein the compound isselected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 7. The method of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 10. The method of claim1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 13. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of a compound of formula Ia:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereofwherein: A, B, C, D, and E are independently N or CR_(x); ------- is anoptional double bond; X is CH or C; U is OH or O; Y and Y′ areindependently H, halogen, or C1-C6 alkyl; R₃ is H; each R_(x) isindependently H, C₁-C₆ alkyl, halogen, —OH, —NHS(O)₂R₁₀, or —OC₁-C₆alkyl; R₁₀ is selected from the group consisting of H; C₁-C₆ alkyloptionally substituted with one or more substituents selected from thegroup consisting of OH, O—C₁-C₅ alkyl, OPO₃ ⁻²M₂, OP(O)(OH)₂,OC(O)alkyl, and OC(O)O-alkyl where M is a monovalent metal cation; andcycloalkyl optionally substituted with one or more substituents selectedfrom the group consisting of OH and O—C₁-C₅ alkyl provided that no morethan one oxygen is attached to any carbon; and L₂ is a bond or(CH₂)_(n), wherein n is 1 or
 2. 14. The method of claim 13, wherein thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 15. A method of modulating NR2B receptors in a subjectcomprising administering to the subject in need thereof an effectiveamount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 16. A method of modulating NR2B receptors in a subjectcomprising administering to the subject in need thereof an effectiveamount of the compound

or a pharmaceutically acceptable salt thereof.
 17. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.
 18. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.
 19. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.
 20. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.
 21. A method ofmodulating NR2B receptors in a subject comprising administering to thesubject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.